Born to have Baby Blues?

It’ s not clear what causes postpartum depression.  The condition, which is marked by persistent feelings of sadness, hopelessness, exhaustion and anxiety, usually begins within four weeks of giving birth and can persist for weeks, months or even up to a year. An estimated 10 to 18% of all new mothers develop the condition, and the rate rises to 30 to 35% among women with previously diagnosed mood disorders.

Scientists have long believed the symptoms were related to the large drop-off in the mother’s estrogen levels following childbirth, however studies have shown that both depressed and non-depressed women have similar estrogen levels.

Now researchers from Johns Hopkins say they have discovered alterations in two genes that, can reliably predict whether a woman will develop postpartum depression.

The genetic modifications, which alter the way genes function without changing the underlying DNA sequence, can apparently be detected in the blood of pregnant women during any trimester, potentially providing a simple way to foretell depression in the weeks after giving birth, and an opportunity to intervene before symptoms become debilitating.

By studying mice, the researchers suspected that estrogen induced genetic changes in cells of the hippocampus – the part of the brain that governs mood.  They  then created a complicated statistical model to find the candidate which could be potential predictors for postpartum depression. That process resulted in the identification of two genes, known as TTC9B and HP1BP3.

Little is known about these genes except for their involvement in hippocampal activity. However the team suspects that they may have something to do with the creation of new cells in the hippocampus and the ability of the brain to reorganize and adapt in the face of new environments. Both of these elements are known to be important in mood.

Furthermore, estrogen can behave like an antidepressant, so when it is inhibited, it adversely affects mood.

“Postpartum depression can be harmful to both mother and child,” says Zachary Kaminsky, Ph.D., an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “But we don’t have a reliable way to screen for the condition before it causes harm, and a test like this could be that way.”

The findings of the small study involving 52 pregnant women are described online in the journal Molecular Psychiatry.

The study involved looking for epigenetic changes tin the thousands of genes present in blood samples from 52 pregnant women with mood disorders. The women were followed both during and after pregnancy to see who developed postpartum depression.

The researchers noticed that women who developed postpartum depression exhibited stronger changes in those genes that are most responsive to estrogen, suggesting that these women are more sensitive to the hormone’s effects. Specifically, changes to the two genes – TTC9B and predicted with 85% certainty which women became ill.

“We were pretty surprised by how well the genes were correlated with postpartum depression,” Kaminsky says. “With more research, this could prove to be a powerful tool.”

Evidence suggests that early identification and treatment of postpartum depression can limit or prevent debilitating effects. Alerting women to the condition’s risk factors — as well as determining whether they have a previous history of the disorder, other mental illness and unusual stress — is key to preventing long-term problems.

Research also shows that postpartum depression not only affects the health and safety of the mother, but also her child’s mental, physical and behavioral health.

If the results of this preliminary work pan out then a blood test for the biomarkers could be added to the battery of tests women already undergo during pregnancy.  More importantly, the results could help to inform decisions about the use of antidepressants. While there are concerns about the effects of these drugs on the fetus and their use should be weighed against the potentially debilitating consequences to both the mother and child of forgoing them.

As Kaminsky says “If you knew you were likely to develop postpartum depression, your decisions about managing your care could be made more clearly.”

Jumping For Joy? Gene Therapy shows promise in Osteoarthritis

As regular readers of SRxA’s Word on Health know, your blogger is one of the estimated 34 million US adults who suffer from osteoarthritis.  The disease, the most common form of arthritis, is characterized by degeneration of cartilage and its underlying bone within a joint as well as bony overgrowth. The breakdown of these tissues eventually leads to pain and joint stiffness. Disease onset is gradual and usually begins after the age of 40, although in some people, myself included, signs and symptoms can appear in your teens or twenties, usually as a result of the wear and tear of repeated sports injuries.

The joints most commonly affected are the knees, hips, hands and spine.

The specific causes of osteoarthritis are unknown, but are believed to be a result of both mechanical and molecular events in the affected joint. Treatment focuses on relieving symptoms and improving function, and can include a combination physical therapy, weight control, medications and joint replacement surgery. But there is currently no cure.

So we were very interested to hear of a new study in mice in which researchers used gene therapy to reduce the risk of osteoarthritis.

And while there’s no way to know if the gene therapy treatment will help humans, or what the treatment’s side effects and costs might be, the findings are more than just good news for mice with creaky joints.

“This work identifies an approach that can make a difference,” explained study co-author Brendan Lee MD, PhD, director of the Rolanette and Berdon Lawrence Bone Disease Program of Texas. “There’s a great need for treating and preventing osteoarthritis.”

His study examined a protein that appears to be crucial to the lubrication of joints.  Researchers injected a gene related to the protein into mice and found that not only did the rodents begin producing it themselves, they also appeared to be resistant to joint and cartilage damage resulting from injury and aging.

Still, before our creaky knees start jumping for joy, as with all early research, there are caveats.

The research was in mice, not humans; the next step is to test the approach in horses, whose joints are similar to those of people. And the gene therapy doesn’t seem to do anything for damage that’s already occurred.

“This kind of therapy would probably not be very useful in patients who have advanced disease,” Lee said, adding that the treatment would likely have to be used with other strategies.

Dr. Joanne Jordan, director of the Thurston Arthritis Research Center at the University of North Carolina at Chapel Hill, said the findings “would be really very exciting if this translates up into humans.” The study, she said, appears to be reasonable and especially strong because it looks at osteoarthritis in the mice from different angles.

We agree. Any research that provides insight into the mechanisms of osteoarthritis development and a potential protective approach to its treatment are very exciting indeed.  A future with no more horse pills sounds good!

Of Mice and Men…and Mental Health

One in five Americans suffers a major depressive episode in their lifetime. Twenty-eight per cent will develop an anxiety disorder, such as post-traumatic stress, phobias, obsessions, or compulsions. Another 15% will fall prey to alcoholism or drug addiction. If you gather 100 people from any square mile on earth, odds are that one will have autism or schizophrenia.

Just about everything we know about drug treatments for psychiatric disorders we learned from mice.  Just how the mouse became our avatar is part tradition and part biological accident. In the past, rats were traditionally used to test experimental drugs. Rats are small enough to be affordable but big enough to make their brains easy to dissect. And they are smarter than mice. You can swiftly teach a rat to solve a maze, for instance, and then test whether your new drug has a side effect of making rats forgetful.

However, rats missed the knockout revolution of the late 1980s. Knockout technology allows researchers to silence, or knock out, individual genes.

With mice, researchers can insert altered DNA in a mouse stem cell, insert the cell in a newly fertilized egg, and insert the egg in a surrogate mother. That egg might develop as a normal mouse or a knockout. The offspring born with knocked-out genes are mated for a few generations to create a pure strain. Once the geneticists perfected these procedures, mice almost instantly assumed the lead role in modeling human mental malfunctions.

These days, you won’t find more mentally ill mice per square mile anywhere than in Bar Harbor, Maine. Mice with anxiety, depression, autism, learning disabilities, anorexia or schizophrenia – they all congregate here. Name an affliction of the human mind, and you can probably find its avatar on this sprucy, secluded island built for America’s richest and most powerful families — including the Rockefellers, the Fords, the Vanderbilts, the Carnegies, the Astors and the Morgans.

The imbalanced mice are kept under the strictest security, in locked wards at the Jackson Laboratory, a nonprofit biomedical facility internationally renowned for its specially bred deranged rodents.

There are no visiting hours, because strangers fluster the mice and might carry in contagious diseases. The animals are attended only by highly qualified caregivers.

But, accurately reproducing a human mental illness in the tiny brain of a mouse is still hugely challenging. The basic structure of a mouse brain is mostly analogous to a human brain.  They have a hippocampus, we have a hippocampus; they have a prefrontal cortex, we have a prefrontal cortex, albeit one that is much larger. We even share about 99% of their genes. But no one would mistake you for a mouse. The mouse is a nocturnal animal with poor eyesight, adapted to fear predators that strike from above. Mice are fundamentally alarmed by light, open spaces, and sudden movements. It is no surprise then, that they manifest depression and anxiety differently than humans do, if they manifest such ailments at all.

“You cannot mimic an entire human psyche in a mouse or a rat,” says 
Jacqueline Crawley, a behavioral neuroscientist at the National Institutes of Health (NIH) “Mice aren’t a one-to-one correspondence to humans. But they are better than zero.”

Disorders like depression and schizophrenia are each linked to hundreds of genes. No one gene is likely to make much difference. But genes are only one part of the story. Other clues to human mental health can be found in the neural circuits of mouse brains. By tracing the wiring that connects one brain region to the next, researchers hope to develop more precisely targeted medications.

Many vintage psychiatric drugs, such as Valium, Ritalin, and antipsychotics, were stumbled upon rather than tailor-made to solve a problem. As a result, they are too broad.  They affect more than one type of receptor, on more than one kind of nerve cell, in more than one part of the brain. Many patients decide the cure is not worth the many side effects.

Mice may be the best models we have of psychiatric disorders, but best does not mean great, or even decent. Gerald Dawson, founder and chief scientific officer of P1Vital, a pharmaceutical consulting firm in the United Kingdom, had his heart broken by the mouse mismatch. In the late 1990s, Dawson set out to eliminate the drowsiness from anxiety drugs.The class of drugs he wanted 
to modify, benzodiazepines such as Valium, Xanax, Ativan, and Klonopin, target the GABAa system.

As with most neurotransmitters, the GABAa system is so evolutionarily ancient that it has diversified to serve many purposes. Hence, the brain has six different GABAa receptor types, presumably to perform six different jobs. Dawson had a suspicion that the sleepiness side effect originated from just one of those six receptors. If he could determine which one, corporate chemists could design a molecule that would avoid activating it. He began to make mice.

One by one, he manipulated the receptor genes, breeding a new line of mice each time. With each new strain, he would administer a tiny dose of Valium. If the animals grew drowsy, he knew he had not yet knocked out the right receptor. Knocking out receptor 1 made little difference. Receptor 3 proved too hard to knock out. Receptor 5 seemed to account for the amnesia that people (and mice) experience when they take anxiety drugs. Targeting receptor 2, Dawson identified a chemical that reduced a mouse’s startle response—a measure of anxiety—without impairing its ability to balance. Success!

Or, so he thought. “When these compounds went into humans, they turned out to be just as sedating as the original drugs.”

Dawson blames the mice. “There’s not enough predictability in animal research.”

But, for all Dawson’s frustration with mice, the rodents did yield a couple of interesting drug leads.

That receptor 5 implicated in the amnesia side effect?  An experimental chemical that blocked its action created temporary geniuses: Mice on it were whizzes in the Morris water maze. A drug company is testing the compound to treat people with Down syndrome. And in the process of trying to eliminate drowsiness, Dawson and his team homed in on one of the chemical switches that cause mammals to go to sleep. Ambien locks onto that switch associated with receptor 1.

So, despite the problems, mice remain the undisputed top animal for research on mental health therapies.

Which just goes to show that mice, like us, have minds of their own.

A Very Happy Christmas for Patients with Christmas Disease

SRxA’s Word on Health couldn’t resist this story. Not only did it provide us with a seasonal healthcare title but it allowed me to blog about a condition that I have been passionate about for most of my life. As a college student, one of my friends and mentors had hemophilia. He taught me a lot about the disease, about courage and dignity and hope and despair. His death from AIDS left me saddened but determined to pursue a career in healthcare. A few years later I had the opportunity to head up a hemophilia research project in the UK. One thing led to another and I spent the next 20 years of my life involved with transfusion medicine and blood products therapies. Although I’m no longer working directly in that field, later today, I will be running a training course on hemophilia.  I guess you could say it’s in my blood!

For those of you wondering what the above recollections have to do with Christmas Disease, let me explain.

Hemophilia B, a deficiency of coagulation factor IX (FIX) is also known as Christmas disease. Hemophilia is an inherited, potentially life-threatening disorder affecting an estimated 20,000 Americans, almost all of them males. Their blood doesn’t clot properly because of a faulty gene. In severe cases, they can spontaneously start bleeding . Internal bleeding in the joints leads to debilitating movement problems and intense pain.

Unlike most diseases that were named after the doctor that discovered them, hemophilia B is rather special because it was named for the first patient described to have it. Stephen Christmas was born in London, UK in 1947.  He emigrated to Canada at a young age and was diagnosed with hemophilia at age two by Toronto’s Hospital for Sick Children. The family returned to London in December 1952 to visit relatives and, during the trip, young Stephen was admitted to hospital. A sample of his blood was sent to the Oxford Hemophilia Centre where it was discovered that he was not deficient in Factor VIII, which is normally decreased in classic hemophilia A, but a different protein, which received the name Christmas factor in his honor (and later Factor IX).

Now, almost 60 years later, scientists have described the first unequivocal evidence of successful gene therapy for hemophilia. Past gene therapy experiments improved blood-clotting for only a few weeks.

This week, the New England Journal of Medicine reports that a single intravenous injection of an adenovirus-associated virus (AAV) vector that expresses FIX  was successfully used to treat 6 patients  with hemophilia B for more than a year. This is a remarkable breakthrough, given that patients normally need to infuse FIX two or more times every week.

The six men each got a single, 20-minute infusion of AAV. Each saw the amount of clotting proteins in their blood increase from less than 1% of normal levels to at least 2%, and in one case as much as 11%.  Although that may not seem like a lot, it was enough to allow all the men to cut back on the number of regular FIX treatments, and four stopped conventional treatment altogether.

Because their prophylactic use of factor concentrate was either eliminated or reduced, dramatic cost savings were achieved. In the United States, annual costs for a single adult patient with hemophilia B are approximately $300,000. Over a lifetime this adds up to a staggering $20 million. Whereas, the AAV is estimated to cost $30,000 per patient

An editorial that accompanied the study asked: Should the practicing hematologist rush to order this gene therapy vector if it is approved by the Food and Drug Administration?

Their answer – “probably yes!”  Still, they caution that the risks of this procedure are not yet totally clear. In one patient, liver enzyme levels were found to be about five times the upper limit of normal 2 months after gene therapy.

Nevertheless this gene therapy trial for hemophilia B is truly a landmark study, since it is the first to achieve long-term expression of a blood protein at therapeutically relevant levels. If further studies determine that this approach is safe, it may not only replace the cumbersome and expensive protein therapy currently used for patients with hemophilia B, but also translate into applications for other disorders, such as alpha₁-antitrypsin deficiency, and hyperlipidemias.

Now, that really would be a Christmas gift.

Tick-tock, tick-tock…we’ll explain your biological clock!

If, like me, you’re one of those people who wake up at exactly the same time every morning without ever setting an alarm clock you’ve no doubt had people ask how you do it? Well, now you can tell them!

According to researchers at the Salk Institute for Biological Studies it’s all in our genes.  Recently they identified a gene responsible for starting our biological clock every morning.

The biological clock ramps up our metabolism early each day, initiating important physiological functions that tell our bodies that it’s time to rise and shine. Discovery of this new gene and the mechanism by which it starts the clock everyday may help explain the genetic underpinnings of sleeplessness, aging, and chronic illnesses such as cancer and diabetes.  Better still, it could eventually lead to new therapies for these illnesses.

“The body is essentially a collection of clocks,” says Satchidananda Panda, an associate professor in Salk’s Regulatory Biology Laboratory, who led the research along with Luciano DiTacchio, a post-doctoral research associate. “We roughly knew what mechanism told the clock to wind down at night, but we didn’t know what activated us again in the morning. Now that we’ve found it, we can explore more deeply how our biological clocks malfunction as we get older and develop chronic illness.”

In a report just published in Science, the Salk researchers and their collaborators at McGill University and Albert Einstein College of Medicine describe how the gene encodes a protein that serves as an activation switch in the biochemical circuit that maintains our circadian rhythm. The discovery fills in a missing link in the molecular mechanisms that control our daily wake-sleep cycle.

It turns out that the molecular bugle call for cells and organs to get back to work each morning is an enzyme known as JARID1a.

Now that scientists understand why we wake each day, they can explore the role of JARID1a in sleep disorders and chronic diseases, possibly using it as a target for new drugs.

SRxA’s Word on Health looks forward to these developments and to a good night’s sleep!

Joint Treatment for Asthma?

Once again, Word on Health brings you news of a potential breakthrough in the treatment of asthma.  Researchers in Australia believe that a drug used to treat rheumatoid arthritis could also help patients with asthma. According to a paper published in the Lancet the scientists from Down Under have identified two mutant genes that may predispose a person to asthma. After comparing 58,000 DNA samples of people living in Australia, Europe and the United States they found two regions of the DNA that are consistently different between asthmatics and non-asthmatics.”  One of the genes is also linked to rheumatoid arthritis (RA) and the researchers suggested that the drug tocilizumab, which is used to treat RA, may also work for asthma. Tocilizumab, marketed under the brand Actemra by Genentech, targets a certain molecule in the body called “interleukin-6 receptor” and reduces inflammation in RA patients. “Targeting interleukin-6 receptor may be a good strategy to reduce or prevent inflammation (in asthma) in the same way that it is used to prevent or reduce inflammation in rheumatoid arthritis,” suggests lead author Manuel Ferreira at the Queensland Institute of Medical Research. Word on Health awaits further research to confirm if and how the drug may help asthma patients. We’ll bring you further news as we hear it.

Found! Fat’s “Master Switch”

Now if only we could find a way to switch it off!

In a breakthrough discovery that has all of us here at Word on Health really excited, scientists have found that a gene that acts as a master switch controlling other genes found in fat tissue.

The study published in Nature Genetics could help to target metabolic diseases such as  obesity, heart disease and diabetes.  More than half a billion people, or one in 10 adults worldwide, are obese. These numbers have doubled since the 1980s as the obesity epidemic has spilled over from wealthy into poorer nations and the trend is expected to continue.

In the United States, obesity-related diseases already account for nearly 10% of medical spending – an estimated $147 billion a year.

Type 2 diabetes, which is often linked to poor diet and lack of exercise, is also reaching epidemic levels worldwide as rates of obesity rise.

The London based research team analyzed more than 20,000 genes in fat samples taken from under the skin of 800 British female twin volunteers. They found the KLF14 gene acts as a master switch to control genes in fat tissues. They confirmed their findings in fat samples from a separate group of people from Iceland.

Genes found to be controlled by KLF14 are linked to a range of metabolic traits, including body mass index, obesity, cholesterol, insulin and glucose levels.

“This is the first major study that shows how small changes in one master regulator gene can cause a cascade of other metabolic effects in other genes,” said lead investigator Tim Spector of King’s College London.

The team are now working hard to see how they can use this information to improve treatment of obesity and obesity-related diseases.

As always we’ll be watching, waiting and writing as soon as we hear more.

High hopes for long-term hemophilia B therapy

Investigators from St Jude Children’s Research Hospital and University College London recently announced extremely encouraging preliminary results of a Phase I/II gene therapy trial in patients with hemophilia B.

Hemophilia B, is a deficiency of Factor IX (FIX), one of the proteins necessary for normal clot formation. The disease affects about 1 in 30,000 people.  Without treatment, people with hemophilia B are at risk for uncontrolled, disabling and potentially fatal episodes of both internal and external bleeding.

The FIX gene is carried recessively on the X chromosome, and as a result the disorder, just like hemophilia A (FVIII deficiency), is almost exclusively seen in males, though it is carried by females.  Patients with severe hemophilia B, must normally inject themselves intravenously with FIX twice a week.

For such patients, gene therapy offers the enticing prospect of a near normal life, but previous studies have yielded disappointing results.

This study, presented last week at the American Society of Hematology annual meeting, was designed primarily to evaluate the toxicological safety study of low and intermediate doses. Because of the low dose used, researchers anticipated that trial subjects would produce little or no detectable FIX. So it was something of a positive surprise when the first patients FIX levels rose from <1% to 2% of normal, after infusion of the experimental vector.

While this rise, may not sound all that impressive, for a person with hemophilia it means the difference between severe and moderate disease.

Even more surprisingly, the patient’s FIX production remains elevated more than nine months later. Since the infusion the patient has also not suffered any spontaneous joint bleeds or needed prophylactic treatment.

Work on the vector began more than 10 years ago. An adeno-associated virus (AAV) vector known as AAV8 was picked because the incidence of natural infection with AAV8 is low and, like although it targets liver cells it does not integrate into the patient’s DNA. Participants received no immune suppressing drugs prior to infusion of the experimental vector.  The results so far suggest the experimental vector does not trigger the T-cell mediated immune response seen in a previous hemophilia B gene therapy trial.

The highest dose of the novel gene-vector combination is scheduled to be infused into the fifth and sixth study participants by mid-January. Investigators will then decide whether to expand the trial to include four more adults with severe hemophilia B.

As always SRxA’s Word on Health will be watching closely and will bring you news of further developments as they are announced.