Research

An Australian study of 136 MS subjects and 272 controls has found connections between red hair-conferring genes, fair skin, sun exposure, and risk of MS. In this study, people with gene variants that result in red hair were more likely to have avoided sun exposure, and women with these variants (but not men) had an increased risk of MS.

People without these variants who had had lower sun exposure as a child had an increased risk of MS. In past studies, low levels of vitamin D, which can be generated through sunlight exposure, have been associated with increased MS risk, which may explain these results. This may be an example where a genetic association with MS (red-hair variants) may come about through changed behavior (sun avoidance) rather than the direct activity of the gene.

The biotech company Centocor (Malvern, PA) and an international team of clinical investigators have just released results from a phase 2 dose-finding trial of its monoclonal antibody drug ustekinumab. Ustekinumab binds to the p40 antigen which is a component of two inflammatory proteins, IL12 and IL23, which have been both detected in MS lesions. It neutralizes these proteins, preventing them from stimulating the production of other inflammatory proteins such as IFN-gamma and IL17. Ustekinumab had been found effective against EAE in pre-clinical trials, and was also found to be safe in phase 1 trials, so the investigators were hopeful that it would help reduce MRI lesion formation and relapses in people with MS.

Unfortunately, none of the doses studied resulted in a significant reduction in lesions or relapses compared with placebo. On the bright side, no permanent serious side effects occurred, and the drug didn't seem to exacerbate MS disease activity (as in the case of TNF-alpha). The authors offered suggestions as to why the drug worked in EAE but not in MS. For instance, while the drug was administered in the early stages of EAE, the MS subjects had a disease duration of two years on average. Alternatively, the pathways targeted by this drug may not be a crucial component of MS disease activity. Either way, it's back to the drawing board.

CIS (clinically isolated syndrome) refers to someone's first MS-like symptom and is a valuable phase of the disease to study. Scientists are interested in learning what causes these initial symptoms to occur in the first place, and why some people with CIS go on to develop MS while others don't.

A team of researchers at UCSF have made some new discoveries about the nature of CIS by using gene expression techniques. They analyzed blood samples of 37 CIS subjects and 29 controls using a gene expression microarray (a chip that analyzes the transcription levels of ~40,000 genes) to see which genes had higher or lower activity in CIS subjects. They found a set of 975 genes that distinguished the CIS subjects from the healthy controls. A number of genes that promote inflammation were downregulated (had lower activity) in the CIS subjects -- this is surprising because MS involves inflammation so one might expect these genes to have higher activity. The researchers also found sets of genes that classified the CIS subjects into four subgroups. One of the subgroups had a higher risk of conversion to MS, so the researchers looked at its gene activity pattern. One of the most underexpressed genes in this subgroup was TOB1 which represses T cell proliferation, suggesting that control of T cell division plays a role in determining whether CIS will develop into MS.

Finally, the scientists analyzed TOB1 gene variants in a group of 1200 MS subjects who had either "mild" or "severe" MS, and found variants that were associated with severity. So regulation of T cell division may also play a role in MS progression.

This paper is open access, so if you like reading scientific papers I recommend checking it out to follow the sequence of steps this team took. It also has an impressive variety of charts and graphs for those who are connoisseurs of visual data representation!

Two studies recently came out that should provide reassurance to pregnant women who have MS or are concerned about MS. An Italian study of 38 pregnant women with MS found that early exposure of the fetus to interferon-beta drugs had no negative effect on the newborn's health status, aside from a slight decrease in birth weight which had no effect on development. So women with MS who become pregnant while taking IFN-b shouldn't be overly concerned that a brief exposure might have harmed their unborn child.

And a large Canadian study of people with MS and spouse controls concluded that pre-term birth does not seem to increase the risk of MS. Pregnant women have enough to worry about -- it's nice that they don't have to worry about these two things.

The results of this study could help dramatically improve the diagnostic work-up in MS with a potential impact on early treatment. The new contrast medium gadofluorine M supposedly visualizes MS lesions better because it binds especially well to certain components of the extracellular matrix of inflammatory foci. Because of this, it accumulates in these lesions in higher concentrations.

It's only been tested in animals so far, but this is one case where the animal models are probably pretty good. It's interesting we haven't seen more work in the contrast medium area.

Preterm birth (birth at less than 37 weeks gestational age) has been shown to result in long-term health problems including impaired neurological development. There were no significant differences between cases and controls with respect to preterm births in this study of 6585 MS index cases and 2509 spousal controls with preterm birth information from the Canadian Collaborative Project on Genetic Susceptibility to MS.

Several studies have reported a reduction of relapses after the long-term administration of IV immunoglobulin (IVIG) to patients with relapsing-remitting multiple sclerosis (RRMS). One hundred twenty-seven patients with RRMS participated in this multicenter, randomized, double-blind, placebo-controlled trial. Although IV immunoglobulin (IVIG) treatment was well tolerated, this study did not substantiate a beneficial effect of IVIG in doses ranging from 0.2 to 0.4 g/kg. This result seriously questions the utility of IVIG for the treatment of relapsing-remitting multiple sclerosis.

Bruce Trapp and his colleagues have published an interesting pathology study of MS brain tissue. (I get very excited every time an MS brain tissue study comes out -- I wish there were more!) In this study, the research team investigated autopsy samples of subcortical lesions (white matter MS lesions located just within the cerebral cortex). Subcortical white matter contains a type of neurons called interneurons -- so-called because they connect to other neurons -- and while they are numerous, they are not as densely packed as neurons in the gray matter are, which makes them easier to study. The scientists analyzed active and chronic subcortical lesions from nine MS subjects, looking for the presence of interneurons.

In the seven active lesions studied, there were no or very few neurons left. The same was true in 44 of the 59 chronic lesions studied. However, the other 15 chronic lesions had an increased number of neurons compared to the neighboring non-lesion areas. Synapses could be seen extending from these neurons, which is appropriate for subcortical white matter neurons. There was also a population of immature neural precursor cells in these lesions. An increased number of precursor cells was found in the subventricular zone bordering demyelinated areas, implying that this region may have been the source of the newly generated interneurons. Finally, these 15 chronic lesions also contained a certain type of activated microglia that was not found in the other lesions.

The findings from this study indicate that unmyelinated neurons like interneurons are destroyed in MS, but in some cases they can be replaced, most likely by migrating precursor cells. Why this happens in some lesions but not others is not known, but perhaps other cells like microglia present in the lesions play a role in this neurogenesis. At any rate, signs of regeneration are encouraging, and hopefully these results can eventually lead to strategies to encourage rebuilding of damaged tissue.

Harvard and Columbia scientists have for the first time used a new technique to transform an ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease) patient’s skin cells into motor neurons, a process that may be used in the future to create tailor-made cells to treat the debilitating disease. The research – led by Kevin Eggan, Ph.D. of the Harvard Stem Cell Institute and Chief Scientific Officer of the New York Stem Cell Foundation – will be published July 31 in the online version of the journal Science.

This is the first time that skin cells from a chronically-ill patient have been reprogrammed into a stem cell-like state, and then coaxed into the specific cell types that would be needed to understand and treat the disease. Though cell replacement therapies are probably still years away, the new cells will solve a problem that has hindered ALS research for years: the inability to study a patient’s motor neurons in the laboratory.

[Editor: Perhaps this technique could be used someday to study cellular differences in people with MS vs. controls.]

As already reported on MSNews, researchers are interested in helminths (parasitic worms) as a potential treatment for MS, based on evidence that they may help prevent MS and/or lead to milder forms of the disease. Results from a recent immunological study may explain why helminth infections could have a beneficial effect on MS.

Scientists studied B cells taken from MS subjects with helminth infections, non-helminth parasitic infections, and no infection, as well as from non-MS controls. They found that the B cells from the helminth-infected MS subjects produced high levels of interleukin-10 (IL-10), an anti-inflammatory signalling molecule. These B cells also produced more brain-derived neurotrophic factor and nerve growth factor than B cells from the other subjects. It may therefore be that helminths protect against MS through a dual action of dampening the immune system and inducing production of neuroprotective factors.