Research News

The Gene Olig1 is required for Myelin Repair within the CNS in Mice

Multiple sclerosis (MS) causes destruction within the central nervous system (CNS) of the nerve's insulating material called myelin. Currently, the strategy to fight the effects of multiple sclerosis consists of preventing and suppressing inflammation. Researchers are now considering an additional therapeutic option: the repair of myelin.

To prevent or limit exacerbations, disease-modifying treatments are aimed at interfering with the destructive events which occur in patients already diagnosed with MS. All of the drugs available today to fight MS focus on this anti-inflammatory process. They are immunomodulators, such as Betaseron® (interferon beta-1b), Avonex® and Rebif® (interferon beta-1a), and Copaxone® (glatiramer acetate), as well as the immunosuppressant Novantrone® (mitoxantrone).

A different way to treat MS focuses on repair. While repairs of the myelin sheath occur naturally after brain or spinal cord injuries (including attacks from MS), new myelin growth is not sufficient to completely repair the damaged tissue and re-establish full myelin function. Consequently, successive exacerbations lead to major destruction of the myelin sheaths, interrupting the flow of nerve impulses, and ultimately causing a loss of function. Despite the importance of myelin repair, little is known clinically and scientifically.

Recently, a study published in the journal Science1 indicated the discovery of a key role played by a gene in the myelin repair. This gene, called Olig1, is required for the repair process. Olig1 produces a protein called a transcription factor. Transcription factors function by regulating the activity of other genes within the nucleus of the cell.

Using mice as a study model, researchers were able to localize the protein produced by this gene. They found that, after damage occurs in the adult nervous system of mice, this protein relocates from the cell body to the nucleus of the cell. This new distribution of the protein into the nucleus indicates that the protein works as a gene regulator. Interestingly, post-mortem studies conducted on six patients with MS revealed, as well, the nucleus localization of this protein in the cells located in regions affected by lesions.

Furthermore, to understand the function of Olig1 in mice, researchers deactivated the gene by genetic technology. This mutated gene was then unable to produce the protein. They discovered that, after artificial brain lesions were developed, these mice lacking Olig1 were incapable of repairing the damaged nervous system. Normally, adult mice are able to repair, to some extent, the damaged nervous system.

These findings clearly indicate that the gene Olig1 is required to repair the damaged myelin. By understanding the molecular process of repair, it may be possible to design specific drugs to stimulate remyelination. For individuals diagnosed with MS, this ability to repair the injured myelin after an exacerbation episode would limit some of the consequences of the injury.

This fundamental discovery provides a fantastic hope for members of the MS community. It is also a step forward to better understand the repair process of the myelin after brain and spinal cord lesions.

- By Christian CD Poncet, PhD
Reviewed by Dr. Jack Burks

Comments and questions are welcome: christianponcet@hotmail.com

1bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. HA Arnett et al, Science, Dec 2004, Vol. 306, 2111-2115.

Tysabri Update: Evaluation Underway, Possible Early Test for Virus, Potential Risks Remain

Several articles on the topic of Tysabri® (natalizumab) and the possible development of progressive multifocal leukoencephalopathy (PML) were posted on the New England Journal of Medicine's website (at http://content.nejm.org) in June 2005. While these case studies and editorials were originally to be published in July 2005, news of a suspected fourth case of PML in a Tysabri-treated patient prompted the journal to post the articles in advance online. Soon after, a possible fifth case of PML was announced in the media.

As of this writing, neither of these "suspected cases" has been officially announced by the FDA or Biogen Idec Inc. and Elan Corp. (makers of Tysabri), so readers are cautioned to wait until these media reports may be confirmed. Additionally, readers should keep in mind that at this time, PML has not been confirmed in anyone taking Tysabri aside from the original three people.

Biogen Idec is conducting a large safety evaluation of thousands of patients who took Tysabri. Any unusual responses to the drug will be investigated and reported to the FDA. Results of this evaluation are expected to be available by the end of the summer.

To review, Tysabri was given early approval in November 2004 by the Food and Drug Administration (FDA) for the treatment of MS. The drug had shown initial success in clinical trials and was expected to be a strong candidate for the treatment of MS. The drug was suspended, however, in February 2005 after PML (an often-fatal brain disorder caused by the activation of the JC Virus) was confirmed in two patients taking both Tysabri and Avonex® (interferon beta-1a).

The first patient died and the second patient is reported to be improving. A third case was discovered upon the re-examination of data on a patient who took Tysabri in the treatment of Crohn's Disease and died in 2003.

A letter from doctors at Biogen Idec may also be viewed on the New England Journal of Medicine's website. They state that while little is known about PML and JC virus, studies suggest that PML is not uniformly fatal, and cases of PML may be preceded by the activation of the JC virus.

The letter also notes that a test may be able to determine the presence of the JC virus in a patient's plasma. The doctors speculate that through early JC Virus detection, Tysabri treatment could be discontinued in time to allow patients to recover, providing hope for some that Tysabri may return to the marketplace.

According to The Wall Street Journal press release dated June 9, 2005, Dr. Joseph Berger from the University of Kentucky Medical Center has some concerns. He warns that while the idea of early diagnosis and recovery is a possibility, the JC virus may still carry associated risks.

For instance, the MS patients with PML were only on Tysabri for two to three years. The risk of developing PML could potentially increase with longer term therapy. Additionally, Tysabri remains in the body for three months after treatment is stopped, which could continue the risk of developing PML, even if the treatment is discontinued following the discovery of the JC Virus. Speculation is not a substitute for data; waiting for the full analysis before making any conclusions will ensure accuracy.

Information for this writing was obtained from the New England Journal of Medicine (at http://content.nejm.org/), Reuters, and The Wall Street Journal.

—Written by Susan Wells Courtney
Reviewed by Dr. Jack Burks

Smoking May Increase Progression of MS

In April 2005, WebMD Medical News reported that researchers from the Harvard School of Public Health have found that individuals with MS who smoke (or smoked previously) appear to be at a much greater risk of experiencing a quicker progression of their disease. While cigarette smoking has already been found to increase one's risk of developing MS, this new research suggests that current and previous smokers are more than three-and-a-half times as likely to progress from relapsing-remitting MS (RRMS) to secondary-progressive MS (SPMS) within a five-year period as compared to patients who never smoked.

These findings came from a study using a national health database from the United Kingdom to identify 179 patients originally diagnosed with RRMS, examining their medical records prior to their diagnosis, confirming their smoking status through computer records, and following their progress. While these findings need to be confirmed though additional research, it does lend support to the value of not smoking.

Researchers have different theories as to why smoking may affect MS. One theory is a link between nitric oxide (a chemical found in cigarette smoke) and MS. Within the body, nitric oxide is a free radical that is suspected of being involved with oligodendrocyte and neuronal injury in MS.

Whether or not the course of one's disease may be changed by quitting cigarettes is not known, but medical professionals agree on the other health benefits derived by not smoking. Further research is needed to confirm the specific dangers of smoking and MS.

—Written by Susan Wells Courtney
Reviewed by Dr. Jack Burks

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