Scientists are seeking to uncover why the immune system attacks healthy cells in lupus. Antinuclear antibodies, like those shown here in lupus-prone mice, are a hallmark of the disease. Photo Courtesy Dr. Mark Shlomchik, Yale School of Medicine
The New York Times, by Andrea Peirce — Lupus, the autoimmune disease, can attack any organ or tissue, including the heart, brain, lungs, kidneys, blood and skin. It is likely that a combination of genes, environmental triggers and hormones set the stage for lupus. Scientists are focusing on new components of the immune system to halt damage from lupus.
Lupus is in many ways the most fundamental of betrayals. The body’s immune system, schooled to identify and purge outside invaders like bacteria and viruses, mistakenly turns its force instead on healthy organs. The result is inflammation and often lasting damage to the heart, lungs, joints, brain, kidneys, blood and skin.
Despite an urgent need to find effective ways to understand and manage lupus, the tool set for doing so has been sparse and simplistic. Nearly a half century has passed since the Food and Drug Administration approved a new lupus treatment. Powerful yet imprecise medicines to control symptoms and complications, like the immune-suppressing steroid prednisone, are all that doctors have had to offer. Medicines to treat lupus are often as damaging as the disease itself.
But in the last five years, the field of lupus investigation has started to percolate. Many experts now say there is realistic hope that techniques and medicines to better monitor and manage the illness will soon emerge.
“This is probably the most promising and exciting time in lupus research, as we tease out the controlling influences of this complex disease and identify the disease drivers that actually lead to abnormalities in the immune system,” said Dr. Lee S. Simon, a former F.D.A. division director and associate clinical professor of medicine at Harvard Medical School.
Much of the new optimism stems from enhanced understanding of how the immune system functions, in health and illness. “We are becoming so much more sophisticated about immunology in general,” said Dr. Betty A. Diamond, head of the Feinstein Institute’s Center for Autoimmune Diseases at the North Shore-Long Island Jewish Health System in New York. “We have identified so many more molecules and pathways leading to lupus, which means so many more pathways and targets for lupus treatments.”
A new array of molecular tools to explore the immune system are now in the hands of medical researchers. And unlike a decade ago, investigators have brought into focus specific immune system components they suspect are involved in the disease. These include the various T cells and antibody-producing B cells that fight invaders. Additional targets include specialized cells and proteins, like the toll-like receptors, interferons and dendritic cells that act as sentinels and goad the immune system into action.
The sequencing of the human genome and techniques that knock out single genes in laboratory animals have shifted interest to the role of genetics as well. Confidence is growing that researchers will identify inherited genes that confer susceptibility to lupus, though most agree that DNA alone is not enough to explain who gets the disease.
External factors almost certainly come into play. A trigger in the environment to jump-start or accelerate the disease process is likely. Under suspicion are elements like exposure to ultraviolet light, crystalline silica used in industry and the Epstein-Barr virus that causes mononucleosis. Since 9 out of 10 lupus patients are women, sex hormones almost certainly play a role.
Identification of early signals of disease flare-ups holds the promise of vastly clarifying what is going on inside the body of the individual with lupus. Researchers are on the hunt for useful markers in the blood or urine. Such biomarkers would be useful for monitoring the effectiveness of new or existing treatments.
Rendering all these discoveries relevant to the person with lupus, however, hinges on bridging the gap between basic science findings and a practical application in humans. We still have to determine the relative benefit to risk of these potentially exciting new therapies.
The F.D.A. has issued guidelines that spell out just what needs to be done to have a lupus medicine approved, a move that has spurred drug makers to step up pursuits of new products. The surge in clinical trials for lupus, from a handful a few years ago to dozens today, suggests that the attempt to translate findings into the tangible care of people with the illness may be close at hand.
Drug-Induced Lupus Erythematosus
- Lupus, Discoid – View of Lesions on the Chest
- Lupus, Discoid on a Child’s Face
- Lupus, Discoid on the Face
The New York Times, by Andrea Peirce — Drug-induced lupus erythematosus is an autoimmune disorder that is brought on by a reaction to medication. New understanding of the immune system aims to halt damage by lupus to the skin, heart, lungs, brain and other organs.
Drug-induced lupus erythematosus resembles systemic lupus erythematosus (SLE). It results from a hypersensitivity reaction to a medication. The drug may react with cell materials, causing the body to form antibodies that attack the body’s own healthy cells.
Several medications are known to cause drug-induced lupus. They include:
Symptoms tend to occur after taking the drug for at least 3 to 6 months.
Persons with drug-induced lupus erythematosus may have symptoms that affect the joints (arthritis), heart, and lungs. Other symptoms associated with SLE, such as lupus nephritis and neurological disease, are rare.
Drug-induced lupus affects men and women equally.
- Blurred vision
- General ill feeling (malaise)
- Joint pain
- Joint swelling
- Loss of appetite
- Pleuritic chest pain
- Skin rash
- Gets worse with sunlight
- “Butterfly” rash across bridge of nose and cheeks
- Weight loss
Exams and Tests
The doctor will listen to your chest with a stethoscope. A sound called a heart friction rub or pleural friction rub may be heard. Signs of pericarditis may be present.
A skin exam shows a characteristic skin rash.
The patient will have taken a medicine linked to drug-induced lupus.
Tests that may be done include:
- Antihistone antibody (often positive in drug-induced lupus)
- Antinuclear antibody (ANA) panel
- Lupus erythematosus cell test (rarely used)
A chest x-ray may show signs of pleuritis or pericarditis. An ECG may show heart involvement.
Usually, symptoms go away within several days to weeks after stopping the medication that caused the symptoms.
Treatment may include:
- Nonsteroidal anti-inflammatory drugs (NSAIDs) to treat arthritis and pleurisy
- Corticosteroid creams to treat skin rashes
- Antimalarial drugs (hydroxychloroquine) to treat skin and arthritis symptoms
Occasionally, the steroid prednisone is used to treat more severe cases, especially if the heart is involved.
Very rarely, high doses of steroids and immune system suppressants, such as azathioprine or cyclophosphamide, are used to treat persons with severe drug-induced lupus that affects the heart, kidney, and neurological system.
Protective clothing, sunglasses, and sunscreen are recommended.
Drug-induced lupus erythematosus is usually not as severe as SLE. Usually, the symptoms go away within a few days to weeks after stopping the medication.
You should avoid the medication in the future, or symptoms usually return. Routine eye exams are recommended to detect eye complications early.
- Thrombocytopenia purpura — bleeding near the skin surface, resulting from a low number of platelets in the blood.
- Hemolytic anemia
When to Contact a Medical Professional
Call for an appointment with your health care provider if symptoms do not improve after discontinuing the medication that caused the symptoms. You should also call if new symptoms develop.
Be aware of the risk when taking medications that are known to cause this reaction. If symptoms begin to appear, contact your doctor.
Harris ED, Budd RC, Genovese MC, Firestein GS, Sargent JS, Sledge CB. Kelley’s Textbook of Rheumatology. 7th ed. St. Louis, Mo: WB Saunders; 2005:1183, 1598.
Noble J. Textbook of Primary Care Medicine. 3rd ed. St. Louis, Mo: Mosby. 2001:1270.
ScienceDaily.com — University of Texas Medical Branch researchers have uncovered an association between free radical-mediated reactions and the severity and progression of system lupus erythematosus (SLE). Higher levels of oxidative and nitrosative stress markers were found in SLE patients with greater disease activity suggesting a causal relationship.
Full findings of the study are available in the July issue of Arthritis & Rheumatism, a journal published by Wiley-Blackwell on behalf of the American College of Rheumatology.
Lupus, an autoimmune disease in which the body’s immune system produces antibodies against itself, causes inflammation, joint pain, fatigue, as well as tissue and organ damage. Approximately 1.5 million Americans and 5 million people worldwide have a form of lupus according to the Lupus Foundation of America with SLE accounting for 70% of all cases. Experts estimate that 70% to 90% of those with this chronic and potentially life-threatening disease are women.
While prior studies have suggested an association between oxidative and nitrosative stress and autoimmunity in mice, its relevance in SLE disease development and progression in humans is not fully understood. To explore the link between reactive oxygen and nitrogen species (RONS) and SLE, M. Firoze Khan, Ph.D., and colleagues used serum from 72 patients (62 female and 10 male) with SLE and 36 healthy control subjects (31 female and 5 male) in their study. The mean age was 47.2 years for the SLE group and 43.1 years in the control. Researchers used the SLE Disease Activity Index (SLEDAI) scores to measure disease activity which ranged from 0 to 38 (mean 10.7). SLE participants were divided into 2 groups — those with a low SLEDAI score of <6 and those with a higher score of ≥6.
Blood levels of oxidative and nitrosative stress markers, including antibodies to malondialdehyde (anti-MDA), 4-hydroxynonenal (anti-HNE), MDA/HNE protein adducts, superoxide dismutase (SOD), nitrotyrosine (NT), and inducible nitric oxide synthase (iNOS) were evaluated in each sample. “Our analysis showed significantly higher levels of anti-MDA and anti-HNE antibodies (biomarkers of oxidative stress) in SLE compared with healthy controls,” said Dr. Khan. Researchers also found that the levels of both these antibodies were significantly higher in lupus patients whose SLEDAI scores were greater than 6, suggesting that increased lipid peroxidation is associated with SLE disease progression.
“Our results clearly show significant increases in oxidative and nitrosative stress in lupus patients suggesting that there is an imbalance between RONS production and antioxidant defense mechanisms in SLE,” concluded Dr. Khan. “Longitudinal studies are needed to further establish how free radical-mediated reactions contribute to SLE development, and to determine the value of anti-MDA and anti-HNE antibodies in assessing the progression and severity of the disease.”
- 1. Gangduo Wang, Silvia S. Pierangeli, Elizabeth Papalardo, G.A.S. Ansari, M. Firoze Khan. Markers of oxidative and nitrosative stress in systemic lupus erythematosus: Correlation with disease activity. Arthritis & Rheumatism, 2010; DOI: 10.1002/art.27442
ScienceDaily.com — A study by researchers in Australia and the United Kingdom suggests that autoantibodies to fat binding proteins significantly increase in systemic lupus erythematosus (SLE) patients with active disease. This increase in anti-apolipoprotein (anti-Apo A-I), anti-high-density lipoprotein (anti-HDL), and anti-C-reactive protein (anti-CRP) may contribute to the development of atherosclerosis in SLE patients, placing them at risk for cardiovascular disease (CVD). Complete findings of this study are available in the March issue of Arthritis & Rheumatism.
Lupus is a chronic autoimmune disease where the immune system creates antibodies that attack an individuals’ own cells, causing inflammation throughout the body. The inflammation leads to tissue and organ damage, affecting the heart, kidneys, lungs, brain, blood, skin and/or joints of those with SLE. According to a 2008 study for the National Arthritis Data Workgroup 322,000 Americans have a definite or probable SLE diagnosis. The Lupus Foundation of America’s figures are much higher, with up to 1.5 million in the U.S. and close to 5 million worldwide reported having form (SLE, discoid, sub-acute cutaneous, drug-induced, or neonatal) of lupus.
In the current study serum levels of anti-Apo A-I, anti-HDL, and anti-CRP were taken from participants that included 39 SLE patients with high disease activity over the previous 2-year period; 42 SLE patients with low disease activity over the previous 2 years; 16 patients newly diagnosed with lupus nephritis (inflammation of the kidney caused by SLE); 25 patients with samples obtained at the time of a SLE flare and during inactivity of the disease; 24 SLE patients who had prior CVD events; and 34 healthy subjects in the control.
Researchers found that antibodies above the upper limit of normal (ULN) were higher in patients in the high disease activity group compared with the low disease activity group: anti-Apo A-I were higher in 35.9% vs. 12% of subjects; anti-HDL levels at 44.7% vs. 30.9%; and anti-CRP at 26.3% vs. 12.8%. Results further indicate that in 55% of the subjects, anti-Apo A-I levels were higher at the time of a disease flare compared with only 34.5% in preflare samples. “The main finding in our study was that levels of anti-Apo A-I and anti-HDL were significantly higher in patients with greater disease activity than in those with less active disease over the same period,” said the authors.
In her editorial also published in Arthritis & Rheumatism, Bevra Hahn, M.D., from the David Geffen School of Medicine at the University of California Los Angeles, acknowledged that the study by O’Neill et al provided a novel method for studying association of autoantibodies with active disease by classifying SLE patients according to sustained chronic disease activity (or not) instead of the traditional approach of using a validated scoring system that identifies active disease at one point in time. “While this is an important step, measuring antibodies to Apo A-I, HDL or CRP in SLE patients has not yet reached the point where it can be used routinely to identify risk of accelerated atherosclerois,” commented Dr. Hahn. “As risk prediction models emerge over the next few years, these antibodies may be included along with other predisposing variables.”
- 1. Sean G. O’Neill, Ian Giles, Anastasia Lambrianides, Jessica Manson, David D’Cruz, Leslie Schrieber, Lyn M. March, David S. Latchman, David A. Isenberg,and Anisur Rahman. Antibodies to Apolipoprotein A-I, High-Density Lipoprotein, and C-Reactive Protein Are Associated With Disease Activity in Patients With Systemic Lupus Erythematosus. Arthritis & Rheumatism, Published Online: February 25, 2010; Print Issue Date: March 2010 DOI: 10.1002/art.27286
- 2. Bevra H. Hahn. Should Antibodies to High-Density Lipoprotein Cholesterol and Its Components Be Measured in All Systemic Lupus Erythematosus Patients to Predict Risk of Atherosclerosis? Arthritis & Rheumatism, February 25, 2010; Print Issue Date: March 2010 DOI: 10.1002/art.27298
These are white blood cells and NETs in a lupus patient. The DNA in NETs is shown in blue; the antibodies binding to the NET are shown in red (fluorescence microscopy). (Credit: Volker Brinkmann)
Max-Planck-Gesellschaft — Lupus is a disease where the immune system attacks healthy cells of the body. This leads to progressive damage of different tissues and organs. The classical characteristic of the disease is the so-called butterfly rash in the face. Many Lupus patients eventually die of kidney failure. Scientists at the Max Planck Institute for Infection Biology in Berlin together with medical scientists from the University of Erlangen succeeded in elucidating basic principles of the disease. This opens up new perspectives for methods that might enable early diagnosis and treatment of Lupus patients with a high risk at kidney failure.
Lupus is one of the most common autoimmune diseases. The symptoms vary from patient to patient and can include rashes, muscle and joint pain, fatigue, inflammation, and miscarriage. One third of the patients die of kidney failure. Little is known about the origin and the pathogenesis of this disease. Diagnosis is difficult because many symptoms are common with other diseases. The hallmark of Lupus is that the body produces antibodies against its own DNA, certain proteins of the nucleus and of white blood cells. The course of the disease is characterized by flares which are often triggered by infections. After a flare the health of the patient improves but often there are sequelae, resulting in a continuous exacerbation of the disease.
Scientists of the Max Planck Institute for Infection Biology suspected that an immune mechanism that was only recently discovered by them, plays a key role in Lupus: During an infection, white blood cells are stimulated and extrude nets in which they trap and kill pathogens. This NET (an acronym for Neutrophil Extracellular Traps) is composed of exactly those components against which a Lupus patient produces antibodies: DNA, as well as proteins of the nucleus and the white blood cells. In co-operation with clinical scientists from the University of Erlangen, the Max Planck scientists could show for the first time that, in contrast to healthy persons, a part of the Lupus patients could not degrade NETs after the infection.
The scientists also discovered that NETs are degraded by the enzyme DNase-1, a protein which normally is found in the blood. Lupus patients, however, either lack this enzyme or their DNase-1 is blocked. Further examination of this patient group revealed that the remains of NETs together with the auto-antibodies are deposited in the kidneys of SLE patients. Indeed, the scientists showed a strong correlation between the inability to degrade NETs in Lupus and a high risk of kidney failure. These results provide a starting point for the development of a test that might allow an early diagnosis and treatment of these high risk patients.
- 1. Abdul Hakkim, Barbara G. Fürnrohr, Kerstin Amann, Britta Laube, Ulrike Abu Abed, Volker Brinkmann, Martin Herrmann, Reinhard E. Voll, and Arturo Zychlinsky. Impairment of NET degradation is associated with Lupus nephritis. PNAS, May 3, 2010 DOI: 10.1073/pnas.0909927107
Dr. Stephane Huberty, who suffered from myasthenia gravis for 14 years, has been taking medication for the disease that he and others developed. Photo Credit: Jock Fistick for The Wall Street Journal
Rixensart, Belgium, GoogleNews.com, WSJ.com, September 7, 2010, by John W. Miller — In late May this year, Dr. Stephane Huberty inserted a needle into his upper arm and injected himself with a cloudy white vaccine previously tested only on rats and dogs.
The reason for this desperate measure: Dr. Huberty suffers from myasthenia gravis, a rare neurological condition. It is one of more than 5,000 “orphan” diseases, so called because there are so few sufferers that most pharmaceutical companies are reluctant to invest in cures.
The 48-year-old Belgian doctor, who has had the disease for 14 years, has been taking medication he and others developed, but he can’t find investors to pay for a clinical trial. Pharmaceutical companies and other doctors say his product is unproven. So Dr. Huberty is taking a leaf out of 19th-century science and using himself as a guinea pig.
Dr. Huberty says he feels better, and that the drug hasn’t produced any nasty side effects. Those, he says, are “good signs that we should begin a professional clinical trial on a sufficient number of patients.”
Taking unapproved drugs is also the last resort for thousands of patients who are desperate to get access to new biological, stem-cell and vaccine technologies that are being invented much faster than regulators can certify them.
The Food and Drug Administration, gatekeeper to the lucrative U.S. pharmaceutical market, oversees a laborious approval process that requires drug developers to conduct four phases of trials, involving thousands of patients. It can take as long as 10 years to get a drug approved.
The FDA has become more thorough and demanding over the past two decades, many scientists say.
“How do you define too long? These are drugs going on the market and being used on patients,” says Karin Riley, an FDA spokeswoman. “We have to be convinced the product is safe and effective.”
Drug companies can seek approval for medicines elsewhere, for example through the London-based European Medicines Agency to sell into the European Union. But they usually concentrate their efforts on the FDA because it yields access to the big U.S. market, where drug prices are higher, medical researchers say.
The number of patients on which a prospective drug must be tested has gone from thousands to tens of thousands over the past 20 years, as safety standards have ratcheted upward, creating a $24 billion industry world-wide in conducting medical trials. That has made bringing a drug to market even more expensive and means many possible cures never secure the investment needed to overcome this hurdle.
Every year, thousands of people petition drug companies and research institutes unsuccessfully for the right to bypass the law and undergo unapproved treatments. And Australians, Americans and Europeans are traveling to China to gain access to stem-cell therapy that isn’t yet legal in the West.
The system all these people are trying to circumvent has many defenders. “Pharmaceutical companies are careful with what they invest in because they don’t want to kill anybody,” says Henry Kaminski, chairman of the Department of Neurology and Psychiatry at St. Louis University in Missouri.
The U.S. National Institutes of Health, which gives grants for medical research, has been criticized for not funding enough worthwhile clinical trials. It “has its problems,” Dr. Kaminski says. But, he adds: “It’s easy to say blow up the system. Show me a better way.”
Dr. Huberty, however, isn’t so much trying a new approach as going back to the past. Before World War II, self-testing drugs was a common method for doctors to ensure the safety of their discoveries.
In the 1840s, U.S. dentist Horace Wells tested laughing gas on himself. That same decade, in Scotland, Sir James Young Simpson gave himself chloroform. In the late 19th century, William Halsted and Richard Hall, two American doctors, experimented with morphine and cocaine.
The experiments weren’t always successful. In 1900, an American doctor named Jesse Lazear gave himself yellow fever by letting a mosquito bite him. Rather than developing an immune response, as he’d intended, he died.
And modern doctors still sometimes resort to this approach. In 1982, Australian gastroenterologist Barry Marshall drank bacteria to give himself a stomach ulcer. That led to his discovery of a treatment for ulcers, a discovery for which he shared the Nobel Prize. In 2003, Indian microbiologist Pradeep Seth injected himself with a potential HIV vaccine he was working on. Mr. Seth’s drug is currently in clinical trials.
Dr. Huberty never imagined he would be a human guinea pig. In 1996, at the age of 33, he lived in a wealthy suburb south of Brussels and ran a thriving start-up that custom-designed orthopedic shoes. He drove a 1971 350 SL Mercedes convertible he completely rebuilt. He swam regularly and boxed.
But that April, while at a business fair in Hannover, Germany, he felt sluggish. He saw the red digital clock in his tour bus go double. He wasn’t sure what was wrong, but “there’s nothing in any medical textbooks that says seeing double is good,” he says.
Dr. Huberty pictured last month at home in Rixensart, Belgium, with his wife, Leone, their daughter Isalyne, and his son Arnaud. Photo Credit: Jock Fistick for The Wall Street Journal
Back in Brussels, his symptoms multiplied. Spaghetti fell out of his mouth. His speech became difficult to understand, and laying carpet with his father, he couldn’t get off the floor. Finally, he says, “a friend told me, ‘you need to see a doctor, Doctor.’ ”
A week later, he saw a neurologist, who asked him to crouch then stand up while pushing his hands down on a table. He couldn’t do it.
The diagnosis: myasthenia gravis, or MG.
The disease, which affects one in 5,000 people, is a dysfunction of the immune system, otherwise known as an autoimmune disorder. Myasthenia sufferers produce antibodies that block muscles’ ability to receive nerve signals from the brain. It is similar to multiple sclerosis, which is estimated to affect between one in 1,000 and one in 10,000 people, but less severe. Other autoimmune disorders include diabetes and rheumatoid arthritis.
There is no proven cure for myasthenia. It can be kept under control with a mix of Mestinon (a drug related to toxic nerve gas), surgery, steroids and other drugs. Treatment costs around $30,000 a year. Like with diabetes, the drugs usually require constant scheduling, and patients have to build their lives around the illness.
At first, Dr. Huberty says, his new life disgusted him. “Compared to my lifestyle before, this was awful,” he says. “I gave myself three months to improve, or I would commit suicide.”
Things improved with treatment. His then-girlfriend gave birth to his son, Arnaud. He settled back into running his company, Information Developments for Educational Applications and Systems, which custom-builds $150,000 machines that help orthopedic shoe companies scan and mold special shoes and soles.
But by 2000, he was still not cured. He worried about the likely side effects of too much cortisone, such as brittle bones, easy bruising and heart problems.
He began reading medical papers, and soon seized on the work of J. Edwin Blalock, a professor of medicine at the University of Alabama at Birmingham.
Now 60, Prof. Blalock was a full professor at the age of 34. Recently, he has gained attention from the Nobel Prize committee for his work showing that a person’s immune system intuitively recognizes threats around it. Prof. Blalock calls this “a sixth sense.” He didn’t win a prize but was invited to speak at a Nobel symposium.
In the late 1980s, Prof. Blalock conceived a vaccine that attacks the lymphocytes that produce auto-antibodies. He theorized the vaccine might be able to cure autoimmune diseases.
He needed a disease to test the theory on, and picked myasthenia. In the 1990s, he played around with his new invention, using the vaccine on lab rats in which he caused myasthenia .
Although Prof. Blalock received funding for his work from the U.S. Muscular Dystrophy Association and the National Institutes of Health, he couldn’t interest any companies in trying to develop and test the vaccine on humans.
“I never doubted that the science might work on people, but going through the process was just too daunting,” Dr. Blalock says.
Then he met Dr. Huberty. At their first meeting, in the Dutch city of Utrecht, where Prof. Blalock sometimes teaches, Dr. Huberty bluntly asked if he could take the drug himself. Prof. Blalock said no, it wouldn’t be legal. “He was quite naïve at first,” Dr. Blalock says.
Dr. Huberty didn’t quit. In September 2001, he flew to Alabama to meet with Prof. Blalock. They had a 2 p.m. appointment on Sept. 11. With aircraft grounded that day, Dr. Huberty took a $400 cab ride from Atlanta to Birmingham, a distance of about 230 kilometers. “I think my commitment to making that appointment got his attention,” Dr. Huberty says.
Dr. Huberty made an offer. He would set up a company that would buy the patent for the vaccine. They would go into business together. The company, Curavac, would try to bring a cure for myasthenia to market.
Dr. Huberty set about finding investors. A wealthy neighbor of Prof. Blalock’s seemed promising, then backed down from putting up $250,000. Family, friends and fellow MG sufferers invested money. A pet-owner whose dog had myasthenia gravis put up $150,000.
In 2007, a neighbor of Dr. Huberty in Brussels, who declined to be named, came forward. “You’ve been my neighbor for seven years, so I can trust you,” he says he told Dr. Huberty. He invested €250,000 ($316,816).
In total, more than $1.5 million was donated or invested in the venture.
Dr. Huberty describes Curavac as a “virtual pharma company.” He has hired experts in the field and outsourced the manufacturing work to a certified contracting lab in Marseille, France. His single-story office attached to his house doesn’t look like much, he says, “but it keeps overheads down and we outsource everything to labs.”
Finally, last year, the drug was ready for clinical testing. But it would take another €5 million and a couple of years before this could begin. Despite contacting major biopharmaceutical companies, he couldn’t find the money. Pharma companies say there are simply too many start-ups out there to take risks. “We invest only when the science is proven,” says Roch Doliveux, chief executive of UCB SA, a Belgian biopharma company.
Dr. Huberty decided he couldn’t wait. Last summer, between June and August, he injected himself three times. He felt cured. He was able to swim, go for long walks and even ski. His nanomole-per-liter antibody count, a traditional measure of myasthenia gravis, fell to near normal levels, according to independent hospital records reviewed by The Wall Street Journal.
In late April, he had a relapse. In May, he re-injected himself with a dose six times as strong as before. He now feels better again. “I swam 60 laps yesterday,” he said in a recent interview at his home, as he watched his wife Leonie play with their eight-month old daughter Isalyne.
Still, Curavac needs investors. Dr. Huberty says it will take €20 million and up to 10 years of clinical trials before he can sell the drug on the market.
The market is there, Dr. Huberty says. There are 200,000 myasthenia sufferers and 15,000 diagnosed each year in Europe, the U.S. and Japan. He plans to sell the cure—most likely three to five injections, possibly with a booster injection a few years later, he says—for $30,000 apiece, the same as the cost of one year of conventional treatment. Other drug companies, he says, aren’t interested “because they want a pill they can sell every day. They’re not interested in curing the disease.”
Most of the medical community is less convinced. They say a cure will emerge through more-traditional research projects. Self-injection “is a totally insane idea,” says James Howard, an expert on myasthenia who works at the universities of North Carolina and North Carolina State.
“I’m not saying the vaccine doesn’t work, but testing like that, well, that’s not proper science.” The lower nanomole/liter measure could be due to other factors, or the placebo effect, Dr. Howard says.
Dr. Huberty says he is prepared to inject himself with more of the vaccine. “It took five injections for some dogs [to be cured],” he says. “I am ready to do whatever it takes to help sufferers of myasthenia gravis.”
Paul Greengard with his dog Alpha. Dr. Greengard made a discovery
that could help slow or stop the effects of Alzheimer’s.
Photo Credit: David Goldman for The New York Times
The New York Times, September 7, 2010, by Gina Kolata — In a year when news about Alzheimer’s disease seems to whipsaw between encouraging and disheartening, a new discovery by an 84-year-old scientist has illuminated a new direction.
The scientist, Paul Greengard, who was awarded a Nobel Prize in 2000 for his work on signaling in brain cells, still works in his Rockefeller University laboratory in New York City seven days a week, walking there from his apartment two blocks away, taking his aging Bernese mountain dog, Alpha.
He got interested in Alzheimer’s about 25 years ago when his wife’s father developed it, and his research is now supported by a philanthropic foundation that was started solely to allow him to study the disease.
It was mostly these funds and federal government grants that allowed him to find a new protein that is needed to make beta amyloid, which makes up the telltale plaque that builds up in the brains of people with Alzheimer’s.
The finding, which was published last Thursday in the journal Nature, reveals a new potential drug target that, according to the prevailing hypothesis of the genesis of Alzheimer’s, could slow or halt the devastating effects of this now untreatable disease.
The work involves laboratory experiments and studies with mice — it is far from ready for the doctor’s office. But researchers, still reeling from the announcement two weeks ago by Eli Lilly that its experimental drug turned out to make Alzheimer’s worse, not better, were encouraged.
“This really is a new approach,” said Dr. Paul Aisen, of the University of California, San Diego. “The work is very strong, and it is very convincing.” Dr. Aisen directs a program financed by the National Institute on Aging to conduct clinical trials of treatments for Alzheimer’s disease.
Over the past few years, research on Alzheimer’s has exploded. Now, Dr. Aisen said, about 200 papers on the subject are published each week. There are new scans and other tests, like spinal taps, to find signs of the disease early, enabling researchers to think of testing drugs before patients’ brains are so ravaged. And companies are testing about 100 experimental drugs that, they hope, will fundamentally alter the course of Alzheimer’s disease.
Most of the new drugs focus on an enzyme, gamma secretase, that snips a big protein to produce beta amyloid. The problem in Alzheimer’s is thought to be an overproduction of beta amyloid — the protein is made in healthy brains but, it is thought, in smaller quantities. Its normal role is not certain, but researchers recently found that beta amyloid can kill microbes, indicating that it might help fight infections.
But gamma secretase has crucial roles in the body in addition to making beta amyloid. It removes stubs of proteins left behind on the surface of nerve cells and is needed to make other proteins, so completely blocking it would be problematic. Many scientists think that was what went wrong with the Eli Lilly drug, which, researchers say, took a sledgehammer to gamma secretase, stopping all of its functions. Other companies say their experimental drugs are more subtle and targeted, but they may still affect the enzyme’s other targets.
Dr. Greengard found, though, that before gamma secretase can even get started, the protein he discovered, which he calls gamma secretase activating protein, must tell the enzyme to make beta amyloid. And since that newly discovered protein is used by the enzyme only for beta amyloid production, blocking it has no effect on the other gamma secretase activities.
It turns out that the Novartis cancer drug Gleevec, already on the market to treat some types of leukemia and a rare cancer of the digestive system, blocks that newly found protein. As a consequence, it blocks production of beta amyloid. But Gleevec cannot be used to treat Alzheimer’s because it is pumped out of the brain as fast as it comes in. Nonetheless, researchers say, it should be possible to find Gleevec-like drugs that stay in the brain.
“You could use Gleevec as a starting molecule,” said Rudolph Tanzi, a neurology professor and Alzheimer’s researcher at Harvard Medical School. “You could change the structure a little bit and try analogs until you get one that does what Gleevec does and does not get kicked out of the brain. That’s possible.”
On a clear, cool summer day last week, Dr. Greengard told the story of his discovery. He sat in a brown chair in his office on the ninth floor of an old stone building on the meticulously landscaped grounds of the university, wearing a soft yellow V-neck sweater and thick-soled black shoes. Alpha lay quietly at his feet.
Dr. Greengard’s assistant ordered lunch — cantaloupe wrapped in prosciutto; ravioli filled with pears, mascarpone and pecorino Romano; cherries; and cookies. But Dr. Greengard, caught up in the tale of his science, asked her to hold off bringing in the food.
“I thought, this is just a horrible disease and maybe there is something I can do about it,” he said.
About a decade ago, Dr. Greengard and his postdoctoral students made their first discovery on the path to finding the new protein — they got a hint that certain types of drugs might block beta amyloid production. So they did an extensive screen of drugs that met their criteria and found that one of them, Gleevec, worked. It completely stopped beta amyloid production.
That was exciting — until Dr. Greengard discovered that Gleevec was pumped out of the brain. Still, he found that if he infused Gleevec directly into the brains of mice with Alzheimer’s genes, beta amyloid went away.
“We spent the next six years or so trying to figure out how Gleevec worked” on gamma secretase, Dr. Greengard said. He knew, though, that he was on to something important.
“I had very little doubt about it,” he said. “If I have an idea, I have faith in it, that it must be right.”
The system he discovered — the gamma secretase activating protein — made sense, Dr. Greengard said.
“Gamma secretase belongs to a family of proteins called proteases,” he explained. Proteases chop proteins into smaller molecules. But often proteases are not very specific. They can attack many different proteins. “Obviously, you can’t have that kind of promiscuity in a cell,” Dr. Greengard said. There has to be some sort of control over which proteins are cleaved, and when.
So, Dr. Greengard said, “what evolved is that proteases invariably have targeting proteins that help them decide which proteins to go after.”
That was what he had found: a targeting protein that sets in motion the activity of gamma secretase, which makes beta amyloid. To further test the discovery, he genetically engineered a strain of mice that had a gene for Alzheimer’s, but he blocked the gene for the gamma secretase activating protein. The animals appeared to be perfectly healthy. And they did not develop plaques in their brains.
For Sangram S. Sisodia, an Alzheimer’s researcher at the University of Chicago, that mouse experiment was critical.
“That was the proof of concept,” he said. It meant that Dr. Greengard was correct — the newly discovered protein, when blocked, does not seem to interfere with other crucial functions of gamma secretase.
“That is good news,” Dr. Sisodia said.
As for Dr. Greengard, he said, “I couldn’t be more excited.
“I am sure there will be a fervor in the field.”
About Gleevec (Imatinib)
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec (USA) or Glivec (Europe/Australia/Latin America) as its mesylate salt, imatinib mesilate (INN). It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and other cancers.
It is the first member of a new class of agents that act by specifically inhibiting a certain enzyme that is characteristic of a particular cancer cell, rather than non-specifically inhibiting and killing all rapidly dividing cells.
Gleevec was developed in the late 1990s by biochemist Nicholas Lydon, a former researcher for Novartis, and oncologist Brian Druker of Oregon Health and Science University (OHSU). Other major contributions to imatinib development were made by Carlo Gambacorti-Passerini, a physician scientist at University of Milano Bicocca (http://www.unimib.it), Italy, John Goldman at Royal Hammersmith Hospital in London, UK, and Charles Sawyers of Memorial Sloan-Kettering Cancer Center, who led the clinical trials confirming its efficacy in CML.
Gleevec was developed by rational drug design. After the Philadelphia chromosome mutation and defective bcr-abl protein were discovered, the investigators screened chemical libraries to find a drug that would inhibit that protein. With high-throughput screening, they identified 2-phenylaminopyrimidine. This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib or Gleevec.
Gleevec received FDA approval in May 2001. On the same month it made the cover of TIME magazine as the “magic bullet” to cure cancer.
Gleevec is used in chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. One study demonstrated that Imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-Kit. Experience has shown, however, that imatinib is much less effective in patients with this mutation, and patients with the mutation comprise nearly 90% of cases of mastocytosis. Early clinical trials also show its potential for treatment of hypereosinophilic syndrome and dermatofibrosarcoma protuberans.
Gleevec may also have a role in the treatment of pulmonary hypertension. It has been shown to reduce both the smooth muscle hypertrophy and hyperplasia of the pulmonary vasculature in a variety of disease processes, including portopulmonary hypertension.
In laboratory settings, Gleevec is being used as an experimental agent to suppress platelet-derived growth factor (PDGF) by inhibiting its receptor (PDGF-Rβ). One of its effects is delaying atherosclerosis in mice without or with diabetes.
Tolerability and adverse effects
bcr-abl kinase, which causes CML, inhibited by Gleevec (small molecule).
In the United States, the Food and Drug Administration has approved Gleevec as first-line treatment for CML. Gleevec has passed through Phase III trials for CML, and has been shown to be more effective than the previous standard treatment of α-interferon and cytarabine. Although the long-term side effects of imatinib have not yet been ascertained, research suggests that it is generally very well tolerated. Broadly, side effects such as edema, nausea, rash and musculoskeletal pain are common but mild.
Imatinib is rapidly absorbed when given by mouth, and is highly bioavailable: 98% of an oral dose reaches the bloodstream. Metabolism of imatinib occurs in the liver and is mediated by several isozymes of the cytochrome P450 system, including CYP3A4 and, to a lesser extent, CYP1A2, CYP2D6, CYP2C9, and CYP2C19. The main metabolite, N-demethylated piperazine derivative, is also active. The major route of elimination is in the bile and feces; only a small portion of the drug is excreted in the urine. Most of imatinib is eliminated as metabolites, only 25% is eliminated unchanged. The half-lives of imatinib and its main metabolite are 18 and 40 hours, respectively.It blocks the activity of Abelson cytoplasmic tyrosine kinase (ABL), c-Kit and the platelet-derived growth factor receptor (PDGFR). As an inhibitor of PDGFR, imatinib mesylate appears to have utility in the treatment of a variety of dermatological diseases. Imatinib has been reported to be an effective treatment for FIP1L1-PDGFRalpha+ mast cell disease, hypereosinophilic syndrome, and dermatofibrosarcoma protuberans.
Mechanism of action
There are a large number of TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factor receptor).
In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is now a constitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity.
The active sites of tyrosine kinases each have a binding site for ATP. The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosine phosphorylation. Imatinib works by binding close to the ATP binding site of bcr-abl, locking it in a closed or self-inhibited conformation, and therefore inhibiting the enzyme activity of the protein semi-competitively. This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation.
Imatinib is quite selective for bcr-abl – it does also inhibit other targets mentioned above (c-kit and PDGF-R), but no other known tyrosine kinases. Imatinib also inhibits the abl protein of non-cancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function even if abl tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl. Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions.
Human molar scaffolding Dr. Jeremy Mao has unveiled a technique that directs the body’s stem cells into a scaffolding that will aid in the regeneration of a new tooth. Columbia University Medical Center
Denver Dentist Extracts Teeth Stem Cells For Use in Future Regenerative Medicine
National Institutes of Health’s recent discovery that powerful stem cells exist in teeth give Denver area dental patients’ an easy way to protect their future health and participate in cutting edge regenerative medicine
GoogleNews.com, September 8, 2010 – “As a dentist it is truly remarkable that our Denver area dental office can offer our patients what may prove to be a potential life-saving procedure by simply preserving teeth that would otherwise be discarded”
Englewood, CO (Vocus)
Denver dentists help harvest stem cells in teeth.
Denver Dentists Dr. James DeLapp, Dr. H. Candace DeLapp and Dr. Sarah Parsons are partnering with StemSave™ to offer their Denver area dental patients a chance to bank valuable stem cells for use in future “Regenerative Medical Therapies”. The National Institutes of Health’s recent discovery that powerful stem cells exist in teeth give Denver area dental patients an easy way that “may” protect their future health and participate in cutting edge regenerative medicine.
Regenerative Medicine treatment has been reported to be the future of medicine.
Stem cells found in teeth are extracted by our Denver Colorado Dentists and cryo-preserved enables patients to recover and save very powerful stem cells found in teeth. The recent discovery that stem cells exist in teeth has the potential to transform dentistry and the future of medical treatments. Stem cells are the basis for the emerging field of Regenerative Medicine. There are more than 78 clinical trials involving stem cell treatments underway and the US Military is developing stem cell therapies to treat soldiers wounded in action. The current research being conducted suggests that stem cell therapies “may”, in the future, be able to treat many of today’s most difficult diseases, such as diabetes, Parkinson’s, Alzheimer’s, muscular dystrophy, cancer and many more.
Stem Cells harvested early in life are more valuable
Living stem cells have been routinely found in teeth and for the most part have been discarded after extraction. Stem cells from teeth appear to replicate at a faster rate than stem cells from other tissues.Stem cells in the body age over time and their ability to regenerate slows down and are less effective. The earlier in life that the stem cells are secured the more valuable they are likely to be later in life.
Teeth Eligibility for stem cell preservation
Not all teeth are eligible for stem cell preservation. As an example the tooth needs to have a healthy pulp. It needs to have an intact blood supply and be free from infection, deep cavities and infection. Stem cells may be recovered from patients that are middle aged but the younger you are the better.
Baby teeth and wisdom teeth may be the best source of stem cells
Deciduous teeth or baby teeth may be the best source of stem cells. The incisors that have begun to loosen or the baby canine teeth appear to be the best candidates. The pulps of naturally loosened teeth may not have an adequate blood supply are not indicated. Wisdom teeth between the ages of 16 and 20 years old may be a very good source. The pulp at this stage is large and the potential for viable stems cell is high. Obviously teeth that have root canals or extensive dental treatment are poor candidates.
Future Medical Research may find treatment for certain diseases
“As a dentist it is truly remarkable that our Denver area dental office can offer our patients what may prove to be a potential life-saving procedure by simply preserving teeth that would otherwise be discarded,” said Denver Dentistry’s Dr. James DeLapp. One of Dr. DeLapp’s patient Denver SEO specialist Scott Carvin commented that he did not know stem cells were in teeth and could be a benefit to his family.
What is unique is that StemSave™ patented technology turns your visit to our Denver family dentists office into what we may find to be a potentially live-saving experience. The best candidate for this type of tissue banking is found in children and young adults. Patients should consider banking their stem cells while undergoing procedures such as the extraction of wisdom teeth or baby teeth. These planned dental procedures provide an ideal time to preserve one’s stem cells.
“We are thrilled to partner with these South Denver area dentists, to make harvesting stem cells from teeth easy and affordable, this way everyone can benefit from the powerful medical applications of stem cells,” said Dr. Gregory Chotkowski, Oral Surgeon and president of StemSave™.
StemSave™ is a collaborative effort between stem cell researchers and the dental community to provide families, and individuals an affordable, non-invasive methodology for the recovery and cryopreservation of the powerful and valuable adult stem cells residing within baby teeth, wisdom teeth, permanent teeth for future use in personalized medicine and regenerative medical therapies.
This could end up being true Denver Preventive Dentistry in action and our office encourages interested patients and families to enroll online at StemSave™ and schedule an appointment to discuss further.
Are there current medical treatments available using stem cells?
No… not at this time. However… much research for various diseases involve treatment that may involve stem cells. This new field of medicine most likely will be called “Regenerative Medicine”. Stem cells in the future may be used for tissue replacement or mitigating the tissue rejection seen in transplants.
StemSave provides an affordable and non-invasive method for the recovery and cryo-preservation of the powerful children or adult Stem Cells found in teeth by teaming up with dentists to harvest stem cells during routine dental procedures.
Find out more . . .
more about stem cells from teeth……
POPSCI.com — The loss of a tooth is a minor deformity and a major pain. Although dental implants are available, the healing process can take months on end, and implants that fail to align with the ever-growing jawbone tend to fall out. If only adult teeth could be regenerated, right?
According to a study published in the Journal of Dental Research, a new tissue regeneration technique may allow people to simply regrow a new set of pearly whites.
Dr. Jeremy Mao, the Edward V. Zegarelli Professor of Dental Medicine at Columbia University Medical Center, has unveiled a growth factor-infused, three-dimensional scaffold with the potential to regenerate an anatomically correct tooth in just nine weeks from implantation. By using a procedure developed in the university’s Tissue Engineering and Regenerative Medicine Laboratory, Dr. Mao can direct the body’s own stem cells toward the scaffold, which is made of natural materials. Once the stem cells have colonized the scaffold, a tooth can grow in the socket and then merge with the surrounding tissue.
Dr. Mao’s technique not only eliminates the need to grow teeth in a Petri dish, but it is the first to achieve regeneration of anatomically correct teeth by using the body’s own resources. Factor in the faster recovery time and the comparatively natural process of regrowth (as opposed to implantation), and you have a massively appealing dental treatment.
Columbia University has already filed patent applications in regard to the technology and is seeking associates to aid in its commercialization. In the meantime, Dr. Mao is considering the best approach for applying his technique to cost-effective clinical therapies.
Japanese Create Stem Cells from Wisdom Teeth
GoogleNews.com, August/September 2010 — Japanese scientists said Friday they had derived stem cells from wisdom teeth, opening another way to study deadly diseases without the ethical controversy of using embryos.
Researchers at the government-backed National Institute of Advanced Industrial Science and Technology said they created stem cells of the type found in human embryos using the removed wisdom teeth of a 10-year-old girl.
“This is significant in two ways,” team leader Hajime Ogushi told AFP. “One is that we can avoid the ethical issues of stem cells because wisdom teeth are destined to be thrown away anyway.
“Also, we used teeth that had been extracted three years ago and had been preserved in a freezer. That means that it’s easy for us to stock this source of stem cells.”
The announcement follows the groundbreaking discovery by US and Japanese scientists last year that they could produce stem cells from skin, a finding that was hailed by the Vatican and US President George W. Bush.
Research involving embryonic stem cells — which can develop into various organs or nerves — is seen as having the potential to save lives by helping find cures for diseases such as cancer and diabetes.
But studies on embryos are strongly opposed by religious conservatives, who argue that such research destroys human life, albeit at its earliest stage of development.
In the new research, cells were extracted from the wisdom teeth and developed for about 35 days.
The researchers then tested them and found that they were stem cells, which can develop into various other kinds of human cells, Ogushi said.
As with last year’s skin cell discovery, the Japanese researchers said it would take time to put the use of wisdom teeth into practical use.
Ogushi estimated it would take at least five years to put the method into clinical use such as trial treatments of congenital bone disease.
“Because extractions of wisdom teeth are commonly operated in dental clinics, we can expect a lot of donors of stem cells,” he said.
“That enable us to create stem cells of various genetic codes, eliminating the risk that a body of a patient would reject transplanted tissues or organs,” he added.
He was hopeful that the method would produce stem cells of various genetic codes — reducing the risk that patients’ bodies would reject transplanted tissues or organs.
Theoretically, people who give up their wisdom teeth in their youth could use the stem cells later in life if they need treatment.
The research takes points from last year’s skin cell breakthrough, which was a collaborative effort by researchers at Kyoto University and the University of Wisconsin at Madison.
The Kyoto University team, led by Shinya Yamanaka, generated human stem cells by introducing four genes into a sample of human skin.
Ogushi introduced three of of the four genes identified by Yamanaka into the wisdom teeth.
Japan, the largest spender on scientific research after the United States, in December announced a 10 billion-yen (92 million-dollar) plan to advance stem cell research over five years.
The culprit: human papilloma virus.
HPV, known for causing cervical cancer, is emerging as the leading cause of throat cancer in men.
FORBES.com, September 8, 2010, by Matthew Herper — Martin Duffy, a Boston consultant and economist, thought he just had a sore throat. When it persisted for months he went to the doctor and learned there was a tumor on his tonsils.
Duffy, now 70, had none of the traditional risk factors for throat cancer. He doesn’t smoke, doesn’t drink and has run 40 Boston Marathons. Instead, his cancer was caused by the human papilloma virus (HPV), which is sexually transmitted and a common cause of throat and mouth cancer.
HPV tumors have a better prognosis than those caused by too many years of booze and cigarettes. But Duffy “is in the unlucky 20%” whose cancer comes back, despite rounds of chemotherapy and radiation that melted 20 more pounds off a lean 150-pound frame. Now the cancer has spread throughout his throat, making eating and talking difficult. “I made my living as a public speaker,” he says. “Now I sound like Daffy Duck.” Duffy believes he has only a few months left. “How do you tell the people you love you love them?” he asks.
Most strains of the HPV virus are harmless, but persistent infections with two HPV strains cause 70% of the 12,000 cases of cervical cancers diagnosed annually in the U.S. Other forms of the sexually transmitted virus can cause penile and anal cancer, and genital warts. The HPV throat cancer connection has emerged in just the last few years and is so new that the U.S. government doesn’t track its incidence. Researchers believe it is transmitted via oral sex. But top researchers estimate that there are 11,300 HPV throat cancers each year in America–and the numbers are growing fast as people have been having more sexual partners since the 1960s. By 2015 there could be 20,000 cases.
These big numbers have some top researchers arguing that drugmakers should test whether HPV vaccines now used to prevent cervical cancer in women can also prevent throat infections in boys. Two vaccines, Gardasil from Merck and Australia’s CSL, and Cervarix from GlaxoSmithKline, are U.S. FDA-approved for preventing cervical cancer. Gardasil is approved for use in boys only to prevent genital warts.
Vaccinating boys could stop this meteoric increase in throat cancer. “Clearly, boys need to be vaccinated,” says Marshall Posner, the incoming medical director of head and neck cancer at Mt. Sinai Medical Center in New York. “I want my kids to be vaccinated. I don’t see a downside to these vaccines.”
There’s only one problem: The vaccine manufacturers aren’t terribly hot on the idea. GlaxoSmithKline says it has no plans to study throat cancer. It adds that it is “committed to providing a vaccine specifically designed to protect against cervical cancer in girls and young women.”
Merck, which takes the lead in testing Gardasil, seemed more interested a couple of years ago. In 2008 it funded Maura Gillison, the Ohio State University researcher who established the HPV-throat-cancer link in 2000, to do a pilot study to show that a test could reliably detect HPV infection in the throat. The pilot study was successful. By early 2009 Gillison says that a larger study of the vaccine in throat cancer looked close to being green-lit.
But after Merck agreed to buy rival Schering-Plough for $41 billion in March 2009, interest in a big study seemed to evaporate, Gillison says. In a statement Merck says that “due to competing research and business priorities, we decided not to move ahead with an efficacy study at this time.”
The drugmakers’ reticence probably stems from a fear that a throat-cancer vaccine would be hard to get approved. Papilloma viruses usually cause cancer slowly, causing precancerous lesions that take many years to blossom into full-fledged malignant tumors. Papilloma viruses cause the hornlike growths in rabbits that probably gave rise to myths of “jackalopes” in the American West. In the cervix early abnormal growths can be picked up with a diagnostic test, the Pap smear. Clinical trials of Gardasil and Cervarix took advantage of this, measuring the number of precancerous growths prevented by the vaccines.
But there are no easy-to-detect precancers in the throat. Adolescent boys would have to be followed for decades to see if the vaccine prevented throat cancer, an unlikely scenario. Short of this, studies could look only at the prevention of HPV throat infections, not cancer or cancer precursors directly. Approving a vaccine for wide use based on this type of short-term data would require a leap of faith that the U.S. Food & Drug Administration might not be willing to take.
Top researchers say government needs to step in and fund the long study if drug companies cannot be persuaded to do it themselves. “I’m sorry Merck decided not to do it,” says Posner. “But in the end this is a federal responsibility. It’s a public health issue.”
For his part Martin Duffy thinks that drug companies’ complacent attitude toward throat cancer would be different if more of their employees were in his situation. “It will change real fast,” he says, “if one of their executives comes down with this disease.”