Author Archives: Iqra Mumal, MSc

Switching from Tysabri to Aubagio Can Help Lower Relapse Risk in MS Patients, Phase 4 Trial Shows

Stable patients with multiple sclerosis (MS) who transition from Tysabri (natalizumab) treatment to Aubagio (teriflunomide) have a lower relapse risk, a new study shows. The study, “Reducing return of disease activity in patients with relapsing multiple sclerosis transitioned from natalizumab to teriflunomide: 12-month interim results of teriflunomide therapy,”…

New Compounds Offer Significant Anti-inflammatory, Neuroprotective Benefits in MS Mouse Study

Two newly identified variants of the known pharmaceutical agent chloroindazole showed significant anti-inflammatory and neuroprotective benefits in a mouse model of multiple sclerosis, a new study shows. Multiple sclerosis is an autoimmune, demyelinating disease of the central nervous system with no known cause or cure. Patients with MS characteristically show loss of the myelin sheath, a protective coat in nerve cells that helps increase cell-to-cell signaling. Several studies have suggested that estrogens — a type of hormone — are beneficial to the functioning of the central nervous system, and help regulate the immune system. Thus, they are attractive candidates for the treatment of MS. However, despite their potential to treat MS, estrogen-based therapies can have several undesirable side effects, such as feminizing male recipients and increasing the risk of developing breast and endometrial cancers in females. Interestingly, estrogens work by binding and activating two different types of receptors: the estrogen receptor (ER)α and ERβ. The cancer-inducing effects of estrogens are mediated mainly through estrogen receptor ERα. Hence, therapies that specifically target ERβ can bypass these deleterious effects. Chloroindazole (IndCl), a pharmaceutical agent, has up to 100-fold relative binding affinity for ERβ over ERα. IndCl has been shown previously to have beneficial effects on modulating the immune system and the central nervous system, and inducing myelination of nerve cells in mouse models of MS. Furthermore, IndCl and other ERβ-activating agents directly support the growth, differentiation (maturation), and overall myelination activity of oligodendrocytes, which are the nerve cells that produce the myelin sheath. Therefore, in order to optimize the benefits of IndCl, researchers developed and screened seven novel IndCl analogues for their ability to promote oligodendrocyte survival, growth, and differentiation. These analogues have a molecular structure closely similar to that of IndCl, but interact with estrogen receptors in subtly different ways. Among these seven compounds, researchers found two analogues — IndCl-o-chloro and IndCl-o-methyl — that stimulated growth and differentiation similar to the original IndCl. Next, researchers evaluated the benefits of these compounds in a mouse model of MS — the experimental autoimmune encephalomyelitis (EAE) mouse model — to determine whether they could alter the disease course, white matter pathology (level of demyelination), and inflammation. Results indicated that both compounds “ameliorated disease severity, increased mature OLs [oligodendrocytes], and improved overall myelination in the corpus callosum and white matter tracts of the spinal cord,” researchers wrote. Corpus callosum is a thick band of nerves that connect the left and right side of the brain. White matter tracts connect the cortex (the largest part of the brain) with other areas in the central nervous system. These beneficial effects were accompanied by a reduced production of the toxic, inflammatory molecules interferon-γ and CXCL10. Additionally, IndCl-o-methyl also reduced the levels of peripheral interleukin (IL)-17, a molecule that strongly induces inflammation. Furthermore, IndCl and both analogues upregulated the expression of a compound called CXCL1, which is associated with increased production of oligodendrocytes. Not only were these two newly identified compounds equivalent to IndCl, but the two analogues performed better in reducing disability and encouraging remyelination than the original compound, and without any obvious side effects. “The o-Methyl and o-Chloro IndCl analogues represent a class of ERβ ligands that offer significant remyelination and neuroprotection, as well as modulation of the immune system; hence, they appear appropriate to consider further for therapeutic development in multiple sclerosis and other demyelinating diseases,” the researchers concluded. “We believe we created a drug that does two things really well, modulating inflammation and allowing axon remyelination. No other drug on the market can do these two things simultaneously,” Seema K. Tiwari-Woodruff, said in a press release written by Stacy Kish. Tiwari-Woodruff is the study's lead author. “The most amazing part of the study is that these new analogues of a known estrogen modulator, chloroindazole, are superior in treating mouse model of multiple sclerosis,” she added. The team has patented the analogues, and hopes to begin further pharmacological and toxicity studies soon.

Lemtrada Can Lower Number of B-cells Infiltrating Nervous System and Forming Clumps, Animal Study Shows

Treating mice in a model of multiple sclerosis with Lemtrada (alemtuzumab) prevented the formation of B-cell aggregates in the animals’ central nervous system and disrupted already existing ones, researchers report. The treatment also reduced disease activity when administered at the peak of disease. The study, “Anti-CD52 antibody treatment depletes B…

Tysabri Treatment Lessens Sexual Dysfunction in MS Patients, Study Finds

Treatment with Tysabri (natalizumab) can help lessen sexual dysfunction in patients with multiple sclerosis (MS), a new study shows. The study, “Patient perceived changes in sexual dysfunction after initiation of natalizumab for multiple sclerosis,” was published in the Multiple Sclerosis Journal – Experimental, Translational and Clinical. MS is…

Non-fermentable Fiber Diet Helped Prevent MS in Mice

A diet that incorporates non-fermentable fiber — a common component of a vegetarian diet — during early life can help prevent the onset of autoimmune diseases such as multiple sclerosis (MS), a new study shows. The study, “Dietary non-fermentable fiber prevents autoimmune neurological disease by changing gut metabolic and…

Study Examines Factors That Increase Risk of Progressing from RRMS to SPMS

Age at disease onset, number of early relapses, and the extent of brain damage at baseline can help identify those who are at high risk of progression from relapsing-remitting multiple sclerosis into the secondary progressive phase of the disease, a new study shows. The study with that finding, “The cortical damage, early relapses, and onset of the progressive phase in multiple sclerosis,” was published in the journal Neurology. Relapsing-remitting multiple sclerosis (RRMS) sometimes can evolve into a secondary progressive (SPMS) phase, which is much harder to treat. Unfortunately, the progression from RRMS to SPMS is largely unpredictable as little is known about the mechanisms that lead to the development of SPMS. A lack of predictive biomarkers also makes it more difficult to identify patients at risk of developing SPMS, who consequently would require much more aggressive therapies. The brain is divided into two types of tissue — white matter and gray matter. Injury to the gray matter of the brain plays a major role in the accumulation of long-term disability in patients with MS. In particular, studies have suggested that cortical lesions and cortical atrophy — representing damage to a part of the brain known as the cerebral cortex — can account for the transition to SPMS. In an effort to learn more about the progression to SPMS, researchers set out to investigate the relationship between cortical changes, the number of early relapses, and the long-term course of MS. Researchers assessed a number of parameters, such as the number of cortical lesions, white matter lesions, and cortical thickness at both onset of MS and at follow-up (mean of 7.9 years) in a group of 219 patients with RRMS. After a mean of 6.1 years, researchers determined that 59 patients, or 27 percent, developed SPMS. Patients who had a larger number of cortical lesions at onset had a higher risk of developing SPMS. Specifically, patients with two cortical lesions had a 2.16-fold greater risk of developing SPMS, patients with five cortical lesions had a 4.79-fold greater risk of developing SPMS, and patients with seven cortical lesions or more had a 12.3-fold higher risk of developing SPMS. Patients with more cortical lesions also tended to have a shorter time to SPMS progression. Patients were grouped by early relapse (ER) numbers during the first two years, including the low-ER group (one ER), mid-ER group (two ERs), and the high-ER group (three or more ERs). Patients in the high-ER group compared to the low-ER and mid-ER groups had a larger volume of cortical lesions at onset and developed more cortical lesions. They also had larger volume of white matter lesions, experienced more severe cortical atrophy over time, and progressed to the SPMS more quickly. Statistical analysis showed that an older age at onset, greater baseline cortical lesion numbers, larger white matter lesion volume, early changes in global cortical thickness, and three or more early relapses independently predicted a higher probability of developing SPMS. Researchers hypothesize that this is likely due to the fact that extensive cortical damage at disease onset is associated with high levels of inflammatory activity and predisposes patients to more quickly develop SPMS. Based on the results, the team concluded: “Age at onset, the number of early attacks, and the extent of baseline focal cortical damage can identify groups at high risk of progression who may benefit from more active therapy.”

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