MSQR - V21. N1. Spring 2002
Researchers Identify Gene Link to Multiple Sclerosis Severity
A critical gene called osteopontin, which is involved in the development of multiple sclerosis (MS), has been identified by researchers at Stanford University Medical Center and the University of California at San Francisco (UCSF). Osteopontin is already known to be a factor in the inflammatory immune response characteristic of MS, but now researchers believe it may be positioned at a number of checkpoints in the progression of the disease. The findings could lead to targeted new therapies for MS in the future.
The researchers examined autopsied brain tissue from persons with MS. Lawrence Steinman, MD, of Stanford University stated that this collaborative project was “a direct extension of a 10-year adventure looking at gene expression in the inflamed MS brain to see what is going on in the course of this disease.” With large-scale sequencing, the investigators created a gene library from the brain tissue, looking for genes that appeared most often. “We found an abundance of osteopontin in the MS brains,” said Steinman. Their findings were reported in the November 23, 2001, issue of Science.
Two important pieces of evidence presented in the paper indicate that in an experimental model of MS, the degree of expression of osteopontin may be related to the severity of the disease. First, the researchers determined that osteopontin expression varies with the phase of the disease. By inducing an autoimmune disease in rodents similar to MS in humans, they were able to show that osteopontin expression is most prominent in nerve cells near sites of active lesions during acute disease and relapse, but not during remission.
Second, using genetically altered mice lacking osteopontin, they confirmed that osteopontin affects the course of the disease, demonstrating that manifestations of the disease were significantly less severe in osteopontin-deficient mice. The percentage of remissions was much higher in the osteopontin-deficient mice. Moreover, there were no disease-related deaths in this group. It was suggested that osteopontin may influence the evolution of the MS, determining whether relapses and remissions develop.
“With this finding, a major piece of the puzzle is in place,” said Jorge Oksenberg, PhD, of UCSF. Steinman added that in addition to osteopontin, a number of other genes were found that warrant further examination. (www.ascribe.org)
FDA Approves First Room-Temperature MS Treatment Option
In mid-January, Berlex Laboratories, Inc., the U.S. affiliate of Schering AG, Germany, and Chiron Corporation announced the approval of a new room-temperature formulation of Betaseron® for subcutaneous injection. Betaseron, the first therapy approved in the US to treat relapsing-remitting MS, will be the first and only MS therapy available as a room-temperature formulation (25°C/77°F), providing a convenient option for patients with MS in the US.
“Because it requires no refrigeration, the new room-temperature formulation provides greater convenience for patients and pharmacies, allowing many more options when traveling and for storage. With fewer potential interruptions in their medication regimen, these patients can continue their treatment and, in many cases, remain active in their endeavors,” said Ralph Makar, Vice President, Marketing, Therapeutics, of Berlex Laboratories.
The new formulation will be available for patients during the middle of 2002. (www1.internetwire.com)
Pirfenidone for Chronic Progressive MS
Current treatment of secondary progressive MS is unsatisfactory in stabilizing or reversing the disabilities associated with the disease. Pirfenidone is a new non-peptide drug that has been shown in vitro and in vivo to decrease synthesis of Tumor Necrosis Factor-alpha (TNF-alpha) and block receptors for TNF-alpha. Since TNF-alpha seems to be a key cytokine in demyelination, a pilot study of oral pirfenidone was undertaken in an open-label baseline versus treatment protocol over a 2-year period in 20 patients. Fourteen patients (70%) remained in the study for 2 years. Three patients dropped out early because of gastrointestinal adverse reactions, and another 3 patients dropped out for personal reasons after 1 year (not due to adverse reactions).
The remaining patients did not manifest any other drug-related adverse reactions and complications. Improvement or stabilization occurred in most patients at about 3 months, and it was sustained at 6, 12, and 24 months as evaluated by both primary and secondary outcome measures. Magnetic resonance imaging (MRI) failed to reveal any new lesions. Thus, pirfenidone appears to offer protection against the usual slow progression of the disease. Most patients experienced a distinct decrease in their neurological disability. These findings indicate that a multi-center, double blind, and placebo-controlled trial is warranted. (Multiple Sclerosis, Oct. 2001, 7(5): 305-312)
Researchers Find Gene Involved in Pain Relief
Researchers in Canada have discovered a genetic mechanism involved in pain modulation that could lead to an entirely new approach to pain control. The results of their research are published in the January 11, 2002, issue of the journal Cell. In the study, genetically engineered mice lacking a gene called downstream regulatory element antagonistic modulator (DREAM) showed a dramatic loss of pain sensitivity compared to mice that had the DREAM gene.
“This is an exciting development,” says study co-author Professor Michael Salter, director of the University of Toronto Centre for the Study of Pain and a senior scientist at The Hospital for Sick Children. “There’s a great deal of interest in this finding because it’s so different from the traditional approaches researchers have been taking to pain management.”
DREAM produces a protein that suppresses the genetic machinery that reads the DNA code for dynorphin, which decreases dynorphin production. Dynorphin is a peptide normally produced in the body. Known as an endorphin, it is produced in response to pain or stress. “We knew about DREAM and its role in dynorphin expression, but the purpose of this study was to determine DREAM’s actual physiological function,” says Salter.
When the DREAM gene was absent in mice, the researchers discovered increased production of dynorphin in the region of the spinal cord involved in transmitting and controlling pain messages. They discovered the mice had decreased sensitivity to acute, inflammatory, and neuropathic pain. “The attenuated pain response was evident for all types of pain in all types of tissue tested,” says Salter. “The fact that even mice with neuropathic pain––the kind of sharp, chronic pain resulting from nerve injury—experienced this effect is exciting because the medical community currently doesn’t have any widely effective treatments for this debilitating type of pain.”
Current approaches to pain management focus on drugs such as morphine
that stimulate cell receptors for the endorphin family of proteins, also
called the endogenous opioid system, or drugs such as aspirin that block
the enzyme cyclo-oxygenase. The DREAM gene, however, works in an entirely
different way by binding directly to DNA and regulating the expression
of a protein in the endogenous opioid system.
The mice in the study that lacked the DREAM gene were otherwise completely normal and showed no reduction in their motor function, learning, or memory. They also did not become addicted to the pain control chemicals their bodies produced, which may prove to be an advantage over the potentially addictive drugs such as morphine, which act on opioid receptors.
“These findings point to a novel pharmacological approach to pain management where researchers will be looking for drugs that could block the ability of DREAM to bind to DNA or simply prevent the production of DREAM,” says Salter. (www.eurekalert.org)
Copaxone® Treatment Reduces Black Holes in the Brain
Black holes are lesions MS can cause in the brain, and these lesions, if permanent, represent areas where the most severe and irreversible brain tissue damage has occurred. A recent study has shown that Copaxone (for injection) reduced by 50% permanent black holes that developed in persons with relapsing-remitting MS.
“This study was designed to determine if glatiramer acetate (Copaxone) could modify the severity of tissue damage in the lesions of MS patients. We know that permanent black holes represent areas with most severe brain damage. The study showed that the drug has the potential to prevent some of the delayed tissue destruction that can follow newly enhanced lesions,” said Jerry S. Wolinsky, MD, Director of the MS Research Group at the University of Texas–Health Science Center in Houston.
The study evaluated 1,722 new lesions from 239 (119 glatiramer acetate, 120 placebo) patients with MS enrolled in the placebo-controlled MRI trial with Copaxone. Investigators monitored these study participants with monthly cerebral MRI scans, which measured the numbers and sizes of several types of lesions in the brain. On subsequent monthly scans, researchers evaluated serial changes in tissues that follow the formation of new enhanced lesions.
“The percentage of black holes on the follow-up scans was lower in Copaxone-treated patients than in placebo after 7 months of follow up,” concluded Massimo Filippi, MD, head of the Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute and the University of Ospedale San Raffaele in Milan, Italy. At month 7, the percentage of lesions that persisted as black holes was 18.9% for patients treated with Copaxone and 26.3% for placebo (p = 0.04). At month 8, the percentage was 15.6% for Copaxone-treated persons and 31.4% for placebo (p = 0.002). (www.acurian.com)
Study Comparing Three MS Therapies Shows Only Two Treatments Yielded Statistically Significant Results in RRMS
Only Copaxone® (glatiramer acetate for injection) and Betaseron® (interferon beta-1b) significantly reduced the mean annualized number of relapses compared to the untreated group of patients with relapsing-remitting multiple sclerosis (RRMS), according to an 18-month prospective, non-randomized, open-label study conducted by researchers at Wayne State University in Detroit, MI.
The primary purpose of the study was to determine the differences in the mean annualized relapse rate of patients with RRMS treated with Copaxone, Betaseron, and Avonex® (interferon beta-1a) compared with those not choosing an immunomodulating therapy. “Foremost, the study indicates that treatment does make a difference and physicians should encourage early treatment,” said Omar Khan, MD, Department of Neurology, Wayne State University School of Medicine.
At the end of the study period, 122 out of 156 study patients with clinically
definite RRMS remained in their original treatment groups. Compared to
the untreated group’s mean annualized relapse rate (1.02), the rate was
reduced for Copaxone-treated patients to 0.49 (p < 0.001) and Betaseron
patients to 0.55 (p = 0.001). The Avonex® group did not show a statistically
significant reduction, 0.81 (p = 0.106).
The mean changes from baseline in expanded disability status scale (EDSS) scores also were reduced significantly compared to untreated patients, only in patients treated with Copaxone (p = 0.003) or Betaseron (p = 0.010).
Dr. Khan indicates this study points to the need for further comparative research on the three currently approved immunomodulating therapies. This study was not intended to be definitive or conclusive as far as the issue of relative efficacy of each immunomodulating therapy is concerned. However, he believes this study provides meaningful information for neurologists treating persons with RRMS. (www1.internetwire.com)
Antibiotic May Be a Potential Therapy for MS
A common antibiotic, long used to treat infections in humans, may have potential as a treatment for MS, according to a new study published in the medical literature in December 2001. The drug, minocycline, is a member of the tetracycline family of antibiotics and was tested in a condition that mimics MS. Study results portray a potential treatment for MS that could significantly decrease the severity of disease attacks or even block the onset of relapses, hence ameliorating many of the disease’s debilitating symptoms.
Minocycline is already used to treat several different infections, but it is also effective in rheumatoid arthritis––an inflammatory condition. Due to this anti-inflammatory property, researchers at the University of Wisconsin-Madison gave minocycline to rats with a disease that closely resembles the inflammatory process of human MS. Senior researcher Ian D. Duncan, PhD, reports that “animals treated with minocycline did not develop nerve problems, or had a less severe case, than did untreated rats. . . . The results also showed that they could treat the animals successfully either before or after the disease began.”
The hope is that minocycline may be able to significantly decrease the
severity of attacks in MS or even block relapses completely. By doing so,
it could relieve many of the symptoms, from paralysis to blindness, that
plague people with this disease. Studies of minocycline in humans with
MS will begin in 2002 at the University of Calgary, Canada. “It is very
important that a well-conducted clinical trial is carried out to test whether
it is safe and effective in MS,” says Duncan. He adds that minocycline
would have advantages over drugs presently used because it is less expensive,
can be taken by mouth, and could be used short-term to stop disease progression.
Copyright © MSQR 2002