THE BIOTECH REVOLUTION – Visions of the Future – BBC
Source: Uploaded by AtheistsAreSkeptics on Sep 30, 2011 to YouTube
THE BIOTECH REVOLUTION – Visions Of The Future – BBC
Genetics and biotechnology promise a future of unprecedented health and longevity: DNA screening could prevent many diseases, gene therapy could cure them and, thanks to lab-grown organs, the human body could be repaired as easily as a car, with spare parts readily available. Ultimately, the ageing process itself could be slowed down or even halted.
Genetically Modified Food – Panacea or Poison
In the last thirty years global demand for food has doubled. In a race to feed the planet, scientists have discovered how to manipulate DNA, the blueprint of life, and produce what they claim are stronger, more disease-resistant crops.
However, fears that Genetically Modified Food may not be safe for humans or the environment has sparked violent protest. Are we participating in a dangerous global nutritional experiment?
This informative film helps the viewer decide if the production of genetically modified food is a panacea for world hunger or a global poison.
Source: UFOTVstudios on YouTube
Epigenetics and Type 2 Diabetes by Rachael Moeller Gorman
Posted August 15, 2009
The New Heredity
By Rachael Moeller Gorman
For hundreds of years, people in the tiny parish of Överkalix, in northern Sweden, have endured bad times and celebrated good ones with little connection to the outside world. To the north and west are Lapps, and to the east, Finns. Though they technically speak Swedish, residents of Överkalix use a dialect that makes them virtually unintelligible to fellow Swedes.
But since the sixteenth century, the people of Överkalix have kept impeccable records of their lives. Clergy logged births, causes of deaths, and land ownership; other historical records noted harvests and crop prices. When epidemiologist Gunnar Kaati arrived 20 years ago, he found an extensive set of meticulous data for this isolated, homogeneous population—a perfect foundation for the large, multigenerational study he hoped to conduct. Kaati wanted to use the data to probe a new idea in clinical medicine—that exposure to certain environments during crucial points in development might determine whether a child would suffer disease years later.
We’re familiar with the notion that the environment is linked to disease—that a diet high in saturated fat may clog arteries and cause heart disease or that radiation mutates DNA and can lead to cancer. But in the emerging field of the fetal and developmental origins of adult disease, more subtle factors such as the amount of food a mother ate during pregnancy or the type of mothering she provided directly after birth may determine whether her child will develop cardiovascular disease or be left neurologically susceptible to overstress years later.
These effects, some researchers believe, have nothing to do with mutations in the DNA code. Rather, they seem to involve what are known as epigenetic changes: structural alterations to the DNA double helix. The notion is that we experience periods in development when our bodies are programmed to collect information about our environment, then readjust our growth depending on what we find. To make this readjustment, our bodies flick genes on or off, sending us on an irreversible trajectory. For example, if a mother doesn’t eat much during pregnancy, that may signal to her fetus that he is about to emerge into a food-poor environment, and he may be born smaller, with a slower metabolism, than if his mother had eaten heartily. Epigenetic changes can lead to, say, type 2 diabetes years later if the world the adult finds—such as a world full of food—is different from that forecast by the fetus.
Kaati took this idea a step further. He wanted to know not just whether a child’s own early environment caused common diseases later in life but whether the environment a child’s parents or even grandparents encountered had an impact. Animal studies suggest that such effects may persist in DNA for generations, and Kaati’s work, still at an early stage, hints that the same thing may happen in humans. Genes might “remember” what our ancestors ate, felt and experienced, altering our own lives generations later.
For many students of biology and evolution, such ideas immediately bring to mind Jean-Baptiste Lamarck, who theorized that traits acquired by an organism during its life can be passed on to its offspring. The classic example is the giraffe that stretches its neck to reach a tree’s top leaves and then gives birth to longer-necked young. Lamarck died 30 years before the 1859 publication of Charles Darwin’s Origin of Species, which detailed evolution as we now know it—a process by which chance differences (later recognized as mutations) improved an individual’s chance of survival and thus ensured the propagation of those traits. Each man proposed a similar result, but by very different mechanisms; in Lamarck’s view, alterations in a species were more immediately driven by environmental change, whereas Darwin saw a longer process of passive natural selection. The subsequent discovery of genes—the primary unit of natural selection— added credence to Darwin’s theory, and Lamarck’s was shelved, seemingly laughable compared with what had been learned about the body’s sophisticated mode of transferring traits.
Yet advances in epigenetic research suggest that Lamarck may have been onto something. As with the giraffe’s tall tree, environmental factors such as lack of food or inattentive mothering appear to alter our epigenomes and sometimes even those of our offspring. (Some researchers think epigenetic changes have helped speed evolution, causing more rapid alterations than could be explained by mutations alone.)
Though Lamarck’s work may have prefigured modern epigenetics, the term itself wasn’t coined until 1942, by a developmental biologist named Conrad Waddington. In Waddington’s view, epigenetics was what we now call developmental biology—the study of how, during development, our genes give rise to our phenotype, the way we look and behave. By the 1990s a new definition had emerged, and today we consider epigenetics the study of changes in gene expression attributable not to alterations in DNA sequence (mutations that change the protein made by a gene) but in DNA structure (alterations to the scaffolding that carries the code, which can turn entire genes off so they make no protein at all).
Though there are several ways these structural changes can happen, the best known—and the focus of most epigenetic research—is DNA methylation, which occurs when a small chemical compound called a methyl group attaches to a cytosine, one of the four nucleotides in the DNA code. Methylation turns off nearby genes in two ways: by blocking transcription factors from attaching to the gene (and thus keeping those factors from translating the gene’s code into a protein) and by altering the configuration of the DNA itself to make the gene less physically available for transcription. (In addition, some recent studies have suggested that methylation may sometimes alter the configuration to turn genes on.) When a cell divides and copies its DNA, it also copies the methyl group, so the same genes remain shut down in the replicated cells.
As an organism develops from a single cell into its final form, epigenetic mechanisms help cells become distinct tissues. So while every cell contains the same DNA code, each type of tissue—hair, heart, brain—differentiates itself through a unique combination of gene expressions. Epigenetic mechanisms turn off the genes that aren’t needed for a particular tissue type and help determine which proteins are expressed.
In recent years research has hinted that epigenetic mechanisms may be responsible for much more than just normal development. Development is inherently plastic, with organisms able to take a number of different paths depending upon the environment into which a fetus was introduced. But once certain developmental decisions are made, they are irreversible. David Barker, a professor of clinical epidemiology at the University of Southampton in England, has studied this idea in humans since the 1990s. In multiple studies he and others have found that babies with birth weights on the lower end of normal who grow up in affluent societies are much more likely to develop coronary heart disease, type 2 diabetes and hypertension as adults than are heavier babies. Barker has theorized that smaller babies are prepared for a diet low in carbohydrates and fat, and when they encounter just the opposite in the real world, they are predisposed to metabolic illnesses.
To see a mismatch between a baby’s real and predicted environment, consider the Dutch famine of 1944–45 and its legacy. When German forces cut off food supplies to parts of the Netherlands for six months, expectant mothers who starved during the final trimester were more likely to have babies who later developed type 2 diabetes. Programmed to expect hard times, these children grew up in an improving postwar environment. Researchers think epigenetic changes might have occurred in genes that regulate sugar absorption and metabolism. Other studies have linked a baby’s environment to kidney problems, asthma, osteoporosis and mental illness as an adult.
All these studies are merely correlational, with researchers noting that certain populations, having undergone a particular environmental stress early in life, have sometimes fallen ill years later. That raises questions of exactly how this may occur, whether epigenetics is the true mechanism and if there is anything to be done about it. While that has yet to be answered conclusively in humans, animal studies may be pointing the way.
For the purposes of epigenetics research, the agouti mouse is particularly apt. Its fur color is determined by the level of methylation on a piece of DNA found near the agouti gene. As a result, genetically identical offspring may look completely different from one another. One mouse might be yellow (indicating little methylation), another brown (a lot of methylation) and a third mottled (some cells with methylated genes, some not).
Randy Jirtle, an epigenetics researcher at Duke University, was intrigued by those tendencies and wanted to know whether early environmental influences could change the mouse’s levels of methylation. In a 2003 experiment, he fed agouti mothers folic acid, vitamin B12, choline and betaine—all methyl supplementers—during pregnancy. This not only increased the babies’ DNA methylation near the agouti gene but also boosted the likelihood that they would be brown, establishing that changes in DNA methylation are the mechanism that connects a mother’s diet to her offspring’s gene expression.
Then, in a 2006 study, Jirtle fed the mothers genistein, a component of soy, and found that it too increased methylation, making the offspring more likely to be brown. Next, he tracked the offspring’s adult weight and found that they were less likely to be obese. That’s because the agouti gene also governs the part of the brain that affects satiation. “The big question is how something that happens early, as a result of benign environmental influences, is linked to susceptibility to common diseases 20 or 30 years later,” says Jirtle. “At least for the agouti mouse, that link is DNA methylation.”
At about the time Jirtle was doing his mice experiments, Michael Meaney, a neuroendocrinologist at McGill University in Montreal, was working with rats, testing the methylation of a gene important to the stress response—a glucocorticoid receptor gene in the brain. It turns out it’s not just what a mother eats but also how she treats her babies that affects their epigenome—the pattern of epigenetic marks that accumulates throughout development. Some rat mothers are particularly attentive to their pups, excessively licking and nursing during the first week after delivery. Studies have shown that the pups of these mothers are less fearful as adults and less fazed by stressful situations.
Meaney found striking differences in methylation patterns between pups with highly attentive mothers and those with neglectful mothers. Less attentive mothering resulted in more methylation near the glucocorticoid receptor gene, turning it off; better mothering kept it on, producing more receptors and better regulation of the rats’ stress response. To confirm his findings, Meaney transferred pups born to neglectful mothers to highly attentive ones immediately after birth; the methylation patterns of these adoptees were almost indistinguishable from those of the attentive mothers’ natural offspring, and the adopted pups grew up to be as fearless as the natural pups. Although these epigenetic changes happened only during one crucial period—the first week after delivery—their impact persisted into adulthood. Yet when Meaney injected a compound into adult rats that demethylated key genes, neglected animals became less fearful. His work provides the first evidence that the way a mother takes care of offspring might change them forever by altering the epigenome.
These studies demonstrate how a less than ideal environment during a critical developmental period may have long-lasting effects. Now, Michael Skinner, a molecular bioscientist at Washington State University in Pullman, is going further, showing that such exposure may change the lives of the altered animals’ descendants too.
Skinner exposed pregnant rats to the toxin vinclozolin, a hormonelike compound known as an endocrine disrupter, during days eight through 15 of their embryos’ development—when the cells that will become sperm are particularly open to epigenetic changes. He found that almost all males in four subsequent generations descended from the vinclozolin-exposed rats had far fewer and less vigorous sperm than normal and were also more likely to be infertile. Moreover, these effects appeared to relate to patterns of DNA methylation.
“The exposure to vinclozolin apparently reprogrammed the remethylation in the male germ line permanently,” Skinner says. In a later study, he found that vinclozolin exposure during the same period not only caused reproductive defects but also led to a number of adult diseases, including prostate disease, kidney disease and tumor development. It even dampened the rats’ chances of finding a mate.
Skinner was the first to show that epigenetics propagates the effects of the environmental exposure of one generation to multiple subsequent generations. “We have a clearly transgenerational effect for four generations and a very high frequency of disease,” he says.
During his years working with the Överkalix data, Kaati has tried to link environmental developments in the parish with possible epigenetic changes in residents. He has followed the lives of people born in 1890, 1905 and 1920 and consulted crop data compiled during the lives of their parents and grandparents. His goal was to find how much food was available to people during one crucial stage of development: the slow growth period (SGP) before puberty begins (between ages eight and 10 for girls and nine and 12 for boys).
In a series of studies published since 2001, Kaati has shown that when food was scarce during a father’s SGP, his son was far less likely to die of cardiovascular disease. And if a paternal grandfather had plenty to eat during his SGP? His grandchild tended to have a shorter life, and his son had a quadrupled risk of dying of diabetes. (These findings may seem to contradict those of Barker and the Dutch famine researchers, yet the crucial difference may be that a child, during his SGP, requires little food, whereas a fetus requires a great deal.) But while these patterns suggest possible epigenetic links, researchers don’t know yet whether there’s a causal connection or which mechanism might be involved. Still, they have their suspicions. “The slow growth period is a time when sperm cells are maturing and during which information is imprinted on those cells,” says Kaati. “For our study’s next phase, we want to see whether these mechanisms extend beyond the three generations we have discovered.”
And if future studies confirm what Kaati and his fellow researchers suspect? “It might be dangerous to overeat during the slow growth period,” he says. “That’s what is happening now, with kids becoming fatter and fatter.” The resulting harm might conceivably persist for generations to come.
But because these studies are preliminary, researchers are cautious. “There’s almost a wish that epigenetic phenomena affect our lives—that when we change our diet, for example, it might change the way our genes are expressed,” says Adrian Bird, a molecular geneticist at the University of Edinburgh who specializes in methylation. “But we have a way to go before we can be sure.”
Several initiatives may boost this research. The National Institutes of Health names epigenetics one of four “grand challenges in biomedical health/research” that “can be uniquely addressed by NIH as a whole.” Therapies that could turn on important genes, especially for the treatment of cancer, are being developed, and some drugs are believed to modify the epigenome for such diseases as epilepsy and bipolar disorder.
There’s also some concern that industrial chemicals may need to undergo testing to make sure they don’t alter the epigenome in a way that could lead to disease. “In the future, we’ll need to test compounds for their ability not only to mutate our DNA but also to alter the epigenome,” says Duke’s Jirtle.
The field of epigenetics may just be dawning, but it could someday change the way doctors approach medicine. “If you think of the genome as a computer’s hardware, then the epigenome is the software that tells the computer how to work,” says Jirtle. “I think we’ll discover that many diseases aren’t the result of hardware problems—mutations—at all. They’ll turn out to be due to software—epigenetic—problems.”
Dossier
1. “Environmental Epigenomics and Disease Susceptibility,” by Randy L. Jirtle and Michael K. Skinner, Nature Reviews: Genetics, April 2007. A thorough review of the environment’s effects on the epigenome, it uses vivid diagrams and photos to illustrate key points.
2. “Transgenerational Response to Nutrition, Early Life Circumstances and Longevity,” by Gunnar Kaati et al., European Journal of Human Genetics, April 2007. The latest in Kaati’s series of fascinating studies on health in an isolated Swedish village shows that food supply during childhood can alter disease risk generations later.
3. Epigenetics? [http://epigenome.eu] This European site tackles the tough field of epigenetics for the general public with in-depth feature stories, frequent updates from the laboratory and the latest news.
Source: Rachael Moeller Gorman
Plant Genetics by Rachael Moeller Gorman
Shoot the Messenger
Proto
Posted June 3, 2009
It all started with petunias. In the mid-1980s, Richard Jorgensen and Carolyn Napoli were working as plant geneticists for an Oakland biotechnology startup that specialized in boosting agricultural yields—increasing frost tolerance with a sort of antifreeze bacteria called Frostban and quickening the ripening of fruits, among other advances. Yet if such improvements were apt to delight farmers, they didn’t always impress potential investors. So the researchers decided to try something more obviously spectacular: creating an extraordinary flower. They chose petunias (Petunia hybrida) because of the plant’s large, colorful blooms and because even then, early in the history of genetic research, scientists had developed sound methods for introducing genes into petunia cells.
In the laboratory, petunias can be grown from single cells, so Jorgensen and Napoli inserted into leaf cells a gene known to produce large amounts of the protein responsible for the flower’s purple pigment. They nurtured the cells into full-grown plants, then transplanted them into soil in a greenhouse. But when the blooms appeared, they were white, not vividly violet. Adding a purple pigment gene had somehow caused the plants to make less of the hue. After ruling out an experimental mishap, they realized an unknown process must be at work.
During the next several years, Jorgensen, Napoli and other plant researchers began to unravel the mysteries of a phenomenon they dubbed co-suppression, a form of gene silencing. But remarkable as it may now seem, the discovery had little impact outside the world of plant research until 1998, when a small team of scientists published a paper detailing a similar type of co-suppression they had discovered in a tiny worm. Interest in this type of gene silencing grew exponentially, and today, 20 years later, the same mechanism that drained the color from petunias is being tested in numerous human clinical trials. It appears capable of remarkable things.
Now known as RNA interference, or RNAi, the mechanism has already transformed the way geneticists figure out the function of genes, sparking “a revolution in our understanding of basic biology,” says Judy Lieberman, a biomedical researcher at Harvard Medical School. But the real excitement involves what RNAi could do outside the laboratory, potentially spawning a vast pharmacopoeia that could selectively eliminate harmful proteins produced by wayward genes in difficult-to-treat diseases.
Unlike gene therapy, which attempts—with limited results—to cure disease by replacing defective genes with properly functioning ones, RNAi allows researchers to tap a pathway that primitive organisms use to turn off invading viruses. Because the workings of the mechanism are natural to the cell, RNAi is theoretically much easier to implement than gene therapy, less invasive (because you’re not actually altering a person’s DNA) and has fewer potential side effects. What’s more, if there are problems, it can be washed from a person’s system.
If RNAi works as researchers hope, it might curb cancer genes; inflammatory genes associated with Crohn’s disease and inflammatory bowel disease, among others; and even genes that cause high cholesterol. Already, there are clinical trials of treatments for AIDS, acute renal failure, respiratory syncytial virus and the wet form of age-related macular degeneration.
Not that there aren’t some very real obstacles, such as simply being able to get a drug carrying an RNAi molecule to the right place in the body and avoiding a massive immune system attack against foreign genetic material. Yet while the hype is huge, the research so far is convincing.
Although known to researchers for decades, RNA had always been considered a mere servant to the more fundamental DNA. Though both kinds of nucleic acid are made of strings of nucleotides, the building blocks of the genetic code that determines every individual’s unique makeup, RNA generally has just one strand of code, while DNA has two. Encapsulated in the cell’s nucleus, DNA holds an organism’s entire archive of genes. To tap that archive, the organism creates RNA, a complementary string of nucleotides that is a copy of a section of DNA code. Exiting the nucleus, the RNA—in this capacity, called messenger RNA, or mRNA—enters the cytoplasm, where the code is translated into proteins.
By the 1990s, scientists had begun to suspect that RNA might play another important role. Craig Mello, at the University of Massachusetts, and Andrew Fire, then at the Carnegie Institution of Washington and now at Stanford University, were intrigued by studies of worms showing that injected RNA could sometimes interfere with the normal protein production coded by a particular gene. So they decided to inject two forms of RNA into Caenorhabditis elegans, a millimeter-long worm often used as a simple model of human disease. The first form was the better-known single-stranded RNA, while the second was a double-stranded cousin (dsRNA) found naturally only in viruses, in which the second strand contains the complementary code sequence of the first (both strands differ somewhat in structure from DNA).
Mello and Fire used this method to introduce extra copies of certain genes into the worm and then tested whether its behavior and appearance had changed. They hypothesized that the genes they had injected would be turned off. In fact, protein production associated with the genes carried by the double-stranded RNA was almost nil. The shutdown was powerfully specific, much more so than that elicited by the single-stranded RNA. It affected only those genes targeted, and it was easy to elicit. They called the effect RNA interference.
Mello and Fire described their worm experiments in the journal Nature, detailing research for which they were awarded the 2006 Nobel Prize in Physiology or Medicine. But it was only later that they and other researchers discovered how RNAi shuts down protein production. It turns out that double-stranded RNA attaches to a cell enzyme called Dicer, which chops the dsRNA (which the cell thinks came from an invading virus) into little pieces. A complex that contains the enzyme Argonaute 2 attaches to the dsRNA. Argonaute 2 splits those pieces into two single strands; one strand remains bound to the complex and eventually finds its corresponding messenger RNA. That mRNA, without this interference, would deliver the genetic code for the gene in question to the cytoplasm’s protein-making machinery, and the protein coded by the gene would be produced. Instead, Argonaute 2 cleaves the mRNA, rendering it useless. Even tiny amounts of dsRNA are enough to slam the door almost completely on protein production.
RNAi also works in fruit flies, plants, zebrafish and other lower organisms, but for several years that seemed to be as far as it went—no one could get RNAi to work in higher organisms. Double-stranded RNA injected into mammals appeared to turn off all genes. But everything finally changed in 2001 with the publication of a paper in Nature by Thomas Tuschl, a co-founder of Alnylam Pharmaceuticals in Cambridge, Mass. He knew that most RNAi experiments used long strands of dsRNA that strung together hundreds of nucleotides. But Tuschl and others had had success with shorter strands, especially in the fruit fly, so he decided to try that approach in mammalian cells.
Eventually it worked. Tuschl found that to trigger RNAi in a mammal’s cell, the physical structure of the double-stranded RNA molecule—known as small interfering RNA, or siRNA—must be precisely constructed. It had to be short, just 21 nucleotides in length, with an overhang of two nucleotides on one or both ends. Using such a molecule in mammals, Tuschl was able to switch off specific genes. “This made what had been an interesting biologic phenomenon in worms relevant to all of us in the medical profession,” says Johannes Fruehauf, vice president of research at Cequent Pharmaceuticals, another RNAi company in Cambridge. “Suddenly there was the prospect of using this process to make a drug.”
Many drugs try to deactivate disease-causing proteins. For example, scientists have engineered small molecules that bind to the active part of a cancer-causing protein and disable it. But only a relatively small number of proteins, probably no more than a few thousand, are treatable by these “small molecule” drugs. Other proteins tend to be inaccessible, with chemical structures not easily targeted. In contrast, with RNAi it’s theoretically possible to design a drug that could turn off any of the 30,000 or so human genes—each of which normally codes for a different protein. “RNAi opens up the possibility that the whole universe of genes becomes ‘druggable,’” says Harvard Medical School’s Lieberman.
There’s another potential advantage. Because many drugs are designed to knock out or alter a particular protein, researchers have to consider the target’s physical structure and model a drug that fits it perfectly. Even then, there’s a chance the drug could react with other, similar proteins. With RNAi, protein targeting becomes both simpler and more precise. Suppose a researcher wants to eliminate production of a protein associated with a particular gene. He could systematically test 21-nucleotide sections of that gene with corresponding dsRNA until he finds one that effectively silences the gene. “This gives you a ready-made drug,” says John J. Rossi of the Beckman Research Institute in Duarte, Calif. “It’s very easy to design siRNA for virtually any gene of interest. And with the whole genome now sequenced, we can identify a target instantaneously.”
A final advantage is that rather than attacking a problem protein, RNAi addresses disease at a fundamental level, turning off the gene that codes for production of that protein. “With RNAi, you’re preventing the protein from even being made, versus trying to mop up the protein’s activity,” says Akshay Vaishnaw, vice president of clinical research at Alnylam.
In 2002 Lieberman began a study attempting to cure HIV in a petri dish of human cells. First, she targeted a protein called CD4, a receptor on the outer membrane of human immune cells, to which the HIV virus attaches itself and into which it inserts its genetic material. Lieberman used siRNA to silence the gene that coded for CD4 and found that without CD4 receptors to bind to, the HIV virus was four times less able to enter a cell. This could halt the spread of the virus.
Next, Lieberman tried a different tack, targeting the virus itself. Using RNAi, she turned off a pivotal HIV gene, called gag, that codes for proteins essential to the virus’s structure. She found that this sharply reduced the amount of HIV in the cells, apparently because new copies of the virus could not be made without the gag gene. Finally, to see whether siRNA could treat infection as well as prevent it, she infected the cells with HIV and then dosed them with siRNA. That worked too.
But treating cells in a petri dish is a far cry from achieving the effect in humans. To see what was possible in a living creature, Lieberman moved on to mice. Because overabundance of a protein called Fas is often involved in liver disease, she designed siRNA for the gene that makes that protein and was able to protect mice with hepatitis from liver failure—the first time siRNA had alleviated disease in an animal.
However, the extraordinary measures she had to employ—injecting a dose of siRNA equal to one-fifth of the mouse’s blood volume at high pressure—would never work in humans. But the following year, a group from Alnylam managed to inject siRNA into a mouse at a normal pressure and volume to silence a gene called apoB, which causes high LDL cholesterol. The researchers altered the siRNA slightly, chemically stabilizing the strands and attaching them to a molecule of cholesterol to make it easier for them to pass into cells. This approach also kept the siRNA from being quickly degraded by enzymes—normally a problem—and the treatment had the desired effect, entering the liver and slowing production of LDL. Alnylam followed up with a 2006 study in primates that also reduced cholesterol.
Yet this success hasn’t really solved the biggest problem of using RNAi to treat human disease. Delivery is the elephant in the room, and progress has been slow. In addition to Alnylam’s cholesterol work, Lieberman is developing an approach using antibodies, while Rossi at the Beckman Research Institute is trying to attach siRNA to a molecule called an aptamer that can bind to various parts of a cell. But none of these has been tested in people yet.
Until the delivery issue is sorted out, researchers say, they’re left to pluck the low-hanging fruit, targeting tissues to which siRNA can be applied directly rather than depending on systemic delivery through the bloodstream. For example, three years ago, Acuity (now called OPKO Health) began the first clinical trial of an siRNA for the wet form of age-related macular degeneration (AMD). Researchers injected siRNA for the gene that codes for the protein VEGF directly into the back of the eye. VEGF causes leaky blood vessels to grow in the eye, damaging the macula—the part of the retina with the most vision cells—and harming the ability to see fine detail. In these small trials, the siRNA proved effective in reducing expression of VEGF. Now, in a larger Phase III trial (the first for an RNAi therapeutic), the siRNA drug is being compared with another AMD drug already on the market.
The lung, reached via inhaled drugs, is also an easy target. Alnylam is conducting a clinical trial that attempts to silence a gene important for the replication of the respiratory syncytial virus (RSV). The company’s main drug, ALN-RSV01, was found to be safe and well tolerated in Phase I trials, and it’s now in Phase II trials to test how well it knocks down the virus in the upper respiratory tract.
For RNAi to live up to its hype, however, researchers will have to find a way to go beyond direct delivery. There are other issues too, not least the worry that siRNAs could trigger a damaging immune response in humans. And what would happen if someone took RNAi drugs for a lifetime, a requirement for many diseases such as HIV or hepatitis? Still, hopes are high. “All of us developing RNAi-based drugs think that this will add a whole new class to our arsenal,” says Fruehauf of Cequent Pharmaceuticals.
Rossi hopes his HIV treatment will be one of those. He has just recruited the first of five patients for a small trial. The patient has lymphoma and AIDS, and as part of the treatment for lymphoma, he’ll receive a blood stem-cell transplant. But before the transplanted cells go into the patient, Rossi will add an anti-HIV siRNA, which “we hope will make the other drugs the patient is on more potent. That could let us lower the dosage of those drugs, or enable patients to go on drug holidays.”
Rossi will follow the patients in his trial indefinitely to monitor whether siRNA continues to combat the virus. But he also thinks RNAi will benefit AIDS patients in another major way. Because HIV mutates rapidly, drugs that were once effective eventually lose potency. RNAi could offer an important answer to this persistent problem. “You could just make a new RNA that would counter the resistance mutation,” he says. “It would be so easy to change the drug. We might even be able to develop an injectable once-a-month treatment using siRNA that would take the place of conventional drugs.”
Source: Rachael Moeller Gorman in “Proto” magazine
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