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Applied Biotechnology, Clinical Trials, FDA, Public Health, Research, Stanford News

The best toxicology lab: a mouse with a human liver

The best toxicology lab: a mouse with a human liver

of mice and menA few years ago, Stanford pharmacogenomic expert Gary Peltz, MD, PhD, collaborating with researchers in Japan, developed a line of bioengineered mice whose livers were largely replaced with human liver cells that recapitulate the architecture and function of a human liver. Now, in a recent study published in PLoS Medicine, Peltz’s team has shown that routine use of this altered lab mouse in standard toxicology tests preceding clinical trials would save human lives.

Among the liver’s numerous other job responsibilities, one of the most important is chemically modifying drugs in various ways to make them easier for the body to get rid of. But some of those chemical products, or metabolites, can themselves be quite toxic if they reach high levels before they’ve been excreted.

The Food and Drug Administration requires that prior to human testing, a drug’s toxicological potential be assessed in at least two mammalian species. But we humans metabolize things differently from other mammals, because our livers are different. That can make for nasty surprises. All too often, drugs showing tremendous promise in preclinical animal assessments fail in human trials due to unforeseen liver toxicity, said Peltz, a former pharmaceutical executive who is intimately familiar with established preclinical testing procedures in the industry.

That’s what happened in 1993 when, after a short safety trial of a drug called FIAU concluded without incident, the comp0und was placed in a phase-2 clinical trial of a drug for hepatitis B. FIAU belongs to a class of drugs that can interfere with viral replication, so it was considered a great candidate for treating virally induced infections such as hepatitis B.

As I wrote in my release about the new study:

“FIAU was supposed to be a revolutionary drug,” Peltz said. “It looked very promising in preclinical tests. In phase 1, when the drug was administered to subjects for a short period of time, the human subjects seemed to do fairly well.” But the phase-2 trial was stopped after 13 weeks, when it became clear that FIAU was destroying patients’ livers.

In fact, nearly half the patients treated with FIAU in that trial died from complications of liver damage. Yet, before advancing to clinical trials FIAU had been tested for as long as six months in mice, rats, dogs and monkeys without any trace of toxicity. An investigation conducted by the National Academy of Sciences later determined that the drug had shown no signs of being dangerous during those rigorous preclinical toxicology tests.

In Peltz’s new study, though, FIAU caused unmistakable early signs of  severe liver toxicity in the bioengineered mice with human livers. This observation would have served as a bright red stop signal that would have prevented the drug from being administered to people.

Bonus item: Using bioengineered mice with human livers instead of mice with murine ones would no doubt result in the clinical and commercial success of some drugs that never got to the human-testing stage because they caused liver toxicity in mice.

Previously: Fortune teller: Mice with ‘humanized’ livers predict HCV drug candidate’s behavior in humans, Alchemy: From liposuction fluid to new liver cells and Immunology escapes from the mouse trap
Photo by erjkprunczyk

Clinical Trials, Health Policy, Research, Science Policy, Stanford News, Videos

New Stanford center aims to promote research excellence

New Stanford center aims to promote research excellence

Updated 4-24-14: The center founders discuss METRICS in this just-posted 1:2:1 podcast.

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4-23-14: Stanford has a new center, called the Meta-Research Innovation Center at Stanford, or METRICS for short, that will focus on ways to transform research practices to improve the reproducibility, efficiency and quality of scientific investigations.
When Stanford professor John Ioannidis, MD, DSc, discusses ideas on how METRICS might improve research quality, he points to the wealth of statistics within any newspaper’s sports section.

“Science needs as many ways to measure performance as sports do,” says Ioannidis. “More important, we need to find efficient approaches for enhancing this performance. There are many ideas on how to improve the efficiency of setting a research agenda, prioritizing research questions, optimizing study design, maximizing accuracy of information, minimizing biases, enhancing reporting of research, and aligning incentives and rewards so that research efforts become more successful. Possibly we can do better on all of these fronts.”

The center’s other co-director is Steven Goodman, MD, MHS, PhD, professor of medicine and of health research and policy.

METRICS’s core group of interdisciplinary scholars will be working on various aspects of meta-research, from methodologies to processes to policy. The center will also provide educational funding for students and scholars; organize collaborative working groups that include academics, policymakers, research funders and the public; and help establish similar initiatives worldwide.

You can learn more about “meta-research” and METRICS’s mission in the short interview above and in this release. Ioannidis discusses the center’s short- and long-term goals in the video clip below.

Previously: The Lancet documents waste in research, proposes solutions, “US effect” leads to publication of biased research, says Stanford’s John Ioannidis and Shaky evidence moves animal studies to humans, according to Stanford-led study
Photo in featured-entry box by Norbert Von Der Groeben

Clinical Trials, Research, Science, Stanford News

SPARK program helps researchers cross the “valley of death” between drug discovery and development

SPARK program helps researchers cross the “valley of death” between drug discovery and development

Mochly-RosenSeveral years ago, Stanford neuroscientist Craig Garner, PhD, found himself facing a common problem for researchers: figuring out how to cross the so-called “valley of death” between drug discovery and development. In his case, he wanted to get pharmaceutical companies interested in funding his lab’s promising new Down syndrome treatment.

The answer was SPARK, a hands-on training program that assists scientists in moving their discoveries from bench to bedside. The program was created by Daria Mochly-Rosen, PhD, after she experienced challenges in getting her own entrepreneurial venture off the ground. A story published in yesterday’s Inside Stanford Medicine explains how Mochly-Rosen and a group of industry experts search hundreds of patents submitted to the university’s Office of Technology Licensing and select projects, such as Garner’s, that could benefit from SPARK’s help. My colleague Ranjini Raghunath writes:

Since SPARK’S founding, 51 research teams have “graduated” from the program. More than half of its projects have been licensed or have advanced to clinical use, or both, in sharp contrast to the pharmaceutical industry’s own success rate of approximately five percent. With SPARK’s support, a research team led by dermatologist Alfred Lane, MD, has received a fund- able score on a food and Drug Administration orphan grant for phase-2 trials of a repurposed drug to treat lymphatic malformations that disfigure and disable children. Another team, led by immunologists William Robinson, MD, PhD, and Jeremy Sokolove, MD, is testing a combination of drugs to treat early stages of cartilage loss and joint degeneration in bone arthritis. findings of a third research team led by bioinformatics expert Atul Butte, MD, PhD, and Bruce Ling, PhD — biomarkers for detecting dangerously high blood pres- sure in pregnancy — have already been picked up for licensing by a start-up biotechnology company. Former SPARK beneficiaries, or “SPARKees,” have credited the program with helping them get research grants, publish papers in reputable journals and even land a tenure-track position, Mochly-Rosen said.

The piece goes on to note that universities around the world have launched, or are developing, their own SPARK programs. Mochly-Rosen’s overall goal for the program is to integrate Stanford and other institutions’ programs under one brand and use it to attract commercial investors to support early-stage research discoveries.

Previously: Director of NIH discusses accelerating translation of biomedical research into clinical applications, Re-engineering the drug-development process to speed medical advances, Why drug development is time consuming and expensive (hint: it’s hard) and A glimpse at the price of drugs: Why they cost what they cost
Photo of Daria Mochly-Rosen by Steve Gladfelter

Autoimmune Disease, Chronic Disease, Clinical Trials, Patient Care

Two decades with scleroderma: How I find answers to hard-to-solve questions

The day I was diagnosed with scleroderma 21 years ago was devastating for my parents and me, to say the least. I was 15 years old and I remember thinking: I have what? Scleroderma? What is that? Can you spell that?

Not much was known about the disease and, since the Internet was in its infancy, we couldn’t simply Google “scleroderma” to learn more about it or find support groups. There was no one to bounce off ideas with. My father, who was a diligent researcher, consulted medical textbooks. Meanwhile, my mother, who was born with the “gift of gab,” sought information from anyone and everyone who crossed her path. But ultimately we were forced to rely heavily on doctors’ recommendations, which sadly were pretty gloomy and a bit much for a teenager to handle.

Fast forward to today. When I have a question, I connect with my local chapter of the Scleroderma Foundation, either by e-mailing a board member or by attending a support group meeting. I also go online to the Raynauds Association, Scleroderma Foundation and Pulmonary Hypertension Association. Above all it’s important to find a rheumatologist who is not only knowledgeable about scleroderma, but has a good grasp of its complexities and is willing to help you get the results you need. Trust me – they are out there!

Back in 2004, I decided it was time to get a new rheumatologist. I asked around for recommendations from my personal network and a friend with rheumatoid arthritis suggested I see her physician. Before meeting the doctor, I looked at his online reviews from other patients and his curriculum vitae to get a sense of his academic and professional experience and achievements. When meeting with a new physician, it’s important to ask if she/he has treated other scleroderma patients, gauge their knowledge of clinical trials, find out if they are up to date on the medications being used to treat the different facets of the disease, and make sure they understand the importance of certain annual tests.

When I switched rheumatologists, I had a particular problem I needed to solve. For the most part my illness had become stable, but I had one pesky ulcer that was truly relentless! I tried various calcium channel blockers, ACE Inhibitors, and Vasodilators, and nothing worked. The infections were getting out of control, even though I did my best to stay on top of it. My frustration reached a point where I asked my doctor to “please, remove the first flange of my index finger.” Thankfully he refused and said, “No, we’re not going to give up.”

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Ask Stanford Med, Chronic Disease, Clinical Trials, Patient Care

Ask Stanford Med: A focus on scleroderma

Ask Stanford Med: A focus on scleroderma

Melissa Warde’s life was forever changed 21 years ago when, at the age of 15, she was diagnosed with scleroderma. At the time, little was known about the chronic connective tissue disease, which involves the hardening and tightening of the skin and fibers that provide the framework and support for the body. “I knew from that day forward, I could sit back and wait for the disease to progress or I could, to the best of my ability, work to control the disease within myself,” Warde said during an Ask Stanford Med Google+ Hangout last week. “I knew I had to have a cheerful disposition, despite the tragedy that I was dealt, and of course having a positive attitude really helped me to focus on the winnings of life.”

During the live conversation, Warde was joined by Lorinda Chung, MD, director of the Scleroderma Center and co-director of the Multidisciplinary Rheumatologic Dermatology Clinic at Stanford, and Karen Gottesman, patient services director for the Scleroderma Foundation of Southern California, for a panel on scleroderma research and progress being made to enhance patients’ quality of life.

Chung opened the discussion with an overview of recent modifications to the disease criteria used in diagnosing scleroderma. Since no two cases of scleroderma are alike, the disease can often be difficult to diagnosis. However, early detection (.pdf) is critical for improving patient outcomes. Under the new criteria, physicians are directed to look for symptoms such as puffy fingers, capillary changes in the nail folds or Raynaud’s disease, which is present in 90 percent of patients with systemic sclerosis. Chung said:

Previously, patients really had to have significant, pretty obvious, skin tightening in order to meet the classification criteria. Or have interstitial lung disease or pulmonary fibrosis, which is scarring in the basis of the lungs, in order to meet the criteria.

These new classification criteria will enable rheumatologists, who may be less experienced in scleroderma, to detect early signs and then refer [patients] appropriately for an accurate diagnosis.

Following Chung’s update on the modifications to the disease criteria, Gottesman spoke about how patients can mange stress related to learning they have a rare, incurable disease and continue living life to the fullest. She advised:

Really learn to be your own advocate. Part of that means educating yourself, not only on all the different aspects of the disease, but also on what type of scleroderma you have so you are aware of possible symptoms that come up.

I think what scares a lot of patients and is really stressful is when you hear of a disease that doesn’t have a cure. But you have to keep in mind that there are hundreds of diseases without cures and we have a lot of treatments in the toolbox to treat the symptoms. At the end of the day you have to learn to co-exist with the disease and that process is really different for every single patient.

Being a proactive patient, Gottesman said, also means being a compliant patient and following through on properly taking any prescribed medications, completing physician recommended tests and other instructions from health-care providers. She said, “If you have a different game plan in mind, then you really need to be upfront [with your doctor] about what it is you need and what you think you want to do, so that you can communicate. That will help you in the long run.”

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Clinical Trials, NIH, Nutrition, Obesity, Research, Stanford News

Stanford seeks participants for weight-loss study

Stanford seeks participants for weight-loss study

Should diets come in different shapes and sizes? Stanford researchers are exploring that question and are seeking participants for a year-long weight-loss study that aims to understand why people may respond differently to the same diet. Titled “One Diet Does Not Fit All,” the study will examine how factors such as genetic influences and eating and sleeping habits have an impact on a diet’s effectiveness.

From a release:

Participants will be assigned randomly to either a very low-fat or very low-carbohydrate diet for 12 months. They will be required to attend weekly classes at Stanford for the first three months, once every other week for the following three months, and once a month for the remainder of the study. Participants must also be willing to have fasting blood samples drawn four times during the 12-month period and participate in online and written surveys. They will receive all test results at the end of the study.

The study is part of a five-year project funded by the National Institutes of Health and the Nutrition Science Initiative. Following an enrollment last year of 200, this spring researchers hope to enroll at least 135 men and women (pre-menopausal only) between the ages of 18 and 50 who are overweight or obese and are generally in good health.

For a complete list of inclusion criteria, click here. To determine eligibility for this study, complete a brief online survey. For more information, contact Jennifer Robinson at nutrition@stanford.edu.

Previously: How physicians address obesity may affect patients’ success in losing weight, To meet weight loss goals, start exercise and healthy eating programs at the same time, The trouble with the current calorie-counting system, Smaller plates may not be helpful tools for dieters, study suggests and Losing vitamins – along with weight – on a diet

Clinical Trials, Nutrition, Science, Stanford News

Bad news for pill poppers? Little clear evidence for Vitamin D efficacy, says Stanford’s John Ioannidis

Bad news for pill poppers? Little clear evidence for Vitamin D efficacy, says Stanford's John Ioannidis

Vitamin DVitamin D is a darling of the supplementation world. Deficiencies in the vitamin have been blamed for all manner of ailments, including diseases of the skeletal system, autoimmunity, infections and cancer.

Now researchers from the University of Edinburgh, Imperial College London and the University of Ioannina School of Medicine in Greece have analyzed 107 systematic literature reviews and 161 meta-analyses regarding vitamin D supplementation or levels in blood plasma and the occurrence of 137 various medical outcomes. They’ve published their findings in today’s issue of the British Medical Journal, where they wrote:

In conclusion, although vitamin D has been extensively studied in relation to a range of outcomes and some indications exist that low plasma vitamin D concentrations might be linked to several diseases, firm universal conclusions about its benefits cannot be drawn.

In particular, the researchers found that the evidence does not support a role for vitamin D in increasing bone mineral density or reducing the risk of falls and fractures in older people. As senior author and Stanford study design expert John Ioannidis, MD, DSc, explained to me in an e-mail:

Vitamin D has been evaluated in thousands of studies in terms of its relationship to at least 137 health outcomes. We hope that systematic consideration of the available evidence will help avoid hot debate about health decisions involving vitamin D  that have mostly depended on speculations rather than evidence to-date.

Rather than writing off vitamin D altogether, the researchers note that additional, well-designed studies and trials are necessary before any firm conclusions can be drawn about its efficacy. The paper is accompanied by a second from researchers at the University of Cambridge analyzing relationships between vitamin D levels and the risk of mortality from several causes, as well as an editorial declaring that, despite much study, vitamin D is “no magic bullet.”

Previously: The Lancet documents waste in research, proposes solutions, “US effect” leads to publication of biased research, says Stanford’s John Ioannidis and Shaky evidence moves animal studies to humans, according to Stanford-led study
Photo by Colin Carmichael

Clinical Trials, Mental Health, Research, Stanford News

Examining an app’s effectiveness at helping those with PTSD

Examining an app's effectiveness at helping those with PTSD

Can a mobile app help people manage the symptoms of post-traumatic stress disorder? As some local readers may have heard on KCBS today (or may remember from a previous Scope entry), this is a question that a group of researchers here are studying.

I explain more about the app in a recent release:

The study involves the use of a Veterans Affairs-developed app designed to provide immediate help for patients’ symptoms. The app contains four sections: “learn,” which provides basic information about PTSD; “find support,” which helps users find professional care; “self-assessment,” which allows users to fill out a survey that measures PTSD symptoms; and “manage symptoms,” which provides tools to address acute symptoms such as insomnia and anger.

The VA-funded trial follows earlier research showing that the decrease in PTSD symptoms for those study participants who used the app for one month was significant when compared to participants in the control group who didn’t use the app. For this study, participants will use the app for three months and fill out online surveys at the start of the study and at the three-month follow-up.

The researchers are looking for 30 participants experiencing symptoms of PTSD; they must not be currently receiving care for the disorder and they must have either an iPhone or Android smartphone on which they can download the app being tested. Those interested in participating or learning more should contact study coordinator Nitya Kanuri at nkanuri@stanford.edu.

Previously: The remarkable impact of yoga breathing for trauma, Relieving stress, anxiety and PTSD with emerging technologies, Using a mobile-based app to help manage PTSD and Stanford and other medical schools to increase training and research for PTSD, combat injuries

Clinical Trials, Dermatology, Pediatrics, Research, Stanford News

Using Viagra to treat a rare childhood deformity: A research update

Using Viagra to treat a rare childhood deformity: A research update

Researchers at Lucile Packard Children’s Hospital Stanford are investigating a surprising treatment for a rare and potentially dangerous childhood deformity. As I’ve described previously, pediatric dermatologist Al Lane, MD, and his colleagues are studying the drug sildenafil – better known by its trade name, Viagra – as a treatment for lymphangioma. The condition, an overgrowth of the body’s lymph vessels, can cause disfigurement and even threaten children’s lives if the deformity impinges on essential body structures such as the airway.

“It can be lethal in 10 percent of people or more, and the problem is, we don’t know what’s the best treatment,” Lane told me.

Other treatments, such as surgery and sclerotherapy, are less effective than doctors would like: Afterward, the deformity often grows back.

A new publication from Lane’s team appeared this week in the Journal of the American Academy of Dermatology, reporting on the first seven patients to have their lymphangiomas treated with sildenafil. Though the idea of giving this drug to children might seem startling, it has a good safety profile and is already used in kids who have a form of high blood pressure in the lungs called pulmonary arterial hypertension. Lane realized that the medication might work for both PAH and lymphangioma when he treated a child with both conditions who was receiving the drug.

The new study shows mixed results. Six of the seven children responded to the medication, though not all responses were equally strong. One child’s deformity became worse while taking the drug. The team is now planning a larger, placebo-controlled, blinded study to investigate why they saw these differences.

“If we can identify which patients respond to sildenafil, we may get a better idea for the molecular mechanism of how it helps, and that could help us understand the disease more,” Lane said.

His team has applied for an orphan disease grant through the National Institutes of Health and the U.S. Food and Drug Administration and will find out in the fall if they’ve been funded.

Previously: Viagra may treat rare childhood deformity

Clinical Trials, Global Health, Infectious Disease, Pediatrics, Stanford News

Life-saving dollar-a-dose rotavirus vaccine attains clinical success in advanced India trial

Life-saving dollar-a-dose rotavirus vaccine attains clinical success in advanced India trial

dollar bill 2Nearly every child in the world has been infected with rotavirus at least once by the age of five. But kids in poor countries get the worst of it. Rotavirus mortality is low in the developed world, but in low-income countries it’s a killer, accounting for 85 percent of the estimated 180,000 to 400,000 annual deaths caused by the pathogen.

The disparity exists for at least two reasons.

First, widespread malnutrition results in a different epidemiology. For example, 70 percent of rotavirus hospitalizations in India happen the first year of life, compared with 40 percent in high- and middle-income countries.

Second, price. Vaccination is second only to gaining access to potable water as a low-cost, high-payoff  strategy for ensuring children’s health. But many vaccines are far too pricey for families living on incomes in the neighborhood of $1,500 per year. As a result, most childhood deaths from vaccine-preventable diseases happen in low-income countries. India has the most rotavirus deaths in the world, estimated at about 75,000-122,000 per year (close to a quarter of the worldwide total.)

So it’s great news that a new rotavirus vaccine developed by Indians for Indians has leaped the safety and efficacy thresholds of a late-stage clinical trial, in which more than 6,500 Indian infants were inoculated, and will likely become available in that country for less than a dollar a dose. (The full immunization procedure requires three separate doses.)

The results appear in a study just published in The Lancet and co-authored by a team including veteran rotavirus-vaccine developer Harry Greenberg, MD. An accompanying perspective piece co-written by Greenberg, who also directs the Stanford Center for Clinical and Translational Research and Education, states:

[P]roof of the efficacy of the… vaccine against a disease that affects almost every child in India, leads to millions of clinic visits and hundreds of thousands of hospital admissions, and kills roughly one child in every 175-200 born in India before their fifth birthday is cause for celebration.

The new vaccine was the first to be fully tested for efficacy in a randomized, double-blind, placebo-controlled clinical trial in India. Interestingly, its development began with the discovery, by an Indian pediatrician, that newborns were getting rotavirus infections in the hospital but not getting sick. The strain they were infected with turned out to be an attenuated mutant virus that turns on the body’s immune response without causing symptoms: in short, the ideal vaccine candidate.

Ultimately spearheaded by a young Indian biotechnology company, Bharat Biotech, the effort to capitalize on this promising episode of serendipity drew financial support from the Bill & Melinda Gates Foundation and technical assistance from the Government of India’s Department of Biotechnology, the United States’ Centers for Disease Control and Prevention, and Stanford, among others.  This international team of collaborators then spent more than 15 years turning the promise into a reality.

Previously: Trials, and tribulations, of a rotavirus vaccine
Photo by David Guo

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