Natalizumab for MS: Why It Helps Some More Than Others – Could Our Genes Be the Reason?
Multiple Sclerosis (MS) is a complex immune-mediated disease where the body's immune system mistakenly attacks the brain and spinal cord. While there's no cure yet, treatments like natalizumab have offered significant hope for many living with this disease. Natalizumab, a type of medication called a monoclonal antibody, works by making it harder for immune cells to enter the central nervous system, thus reducing inflammation. It's been a game-changer for relapsing-remitting MS (RRMS) and shows promise in other forms of MS as well.
However, like many treatments, natalizumab doesn't work perfectly for everyone. Some individuals see a great improvement, while others unfortunately don't experience the same benefits. This raises a crucial question: Why do some people respond better to natalizumab than others?
A study published in the Annals of Clinical & Laboratory Science delved into this question by investigating the potential role of our genes, specifically those involved in protecting our bodies from damage caused by something called oxidative stress.
Oxidative Stress: A Silent Contributor to MS
Think of oxidative stress as an imbalance in the body where harmful molecules called reactive oxygen species (ROS) overwhelm our natural defenses. These ROS can damage cells and are believed to play a significant role in the development and progression of MS. Our bodies have natural detoxification systems, including enzymes like NAD(P)H quinine oxidoreductase 1 (NQO1) and glutathione-S-transferase P1 (GSTP1), that help neutralize these harmful molecules.
The activity of these enzymes can vary from person to person due to tiny differences in their genes, called polymorphisms. These polymorphisms can lead to enzymes that are less efficient at their job. The researchers in this study focused on two specific polymorphisms in the NQO1 and GSTP1 genes known to affect their activity.
Investigating the Link with Natalizumab Response
The study involved 130 individuals with confirmed MS who were receiving monthly natalizumab treatment. The researchers carefully tracked how these patients responded to the treatment, classifying them as "responders" (those with a significant decrease in relapse rate and stable or reduced disability) or "non-responders" (those who showed clinical deterioration).
Next, they analyzed the genetic makeup of these patients, specifically looking at the NQO1 (C609T polymorphism) and GSTP1 (A313G polymorphism) genes. They wanted to see if there was any connection between the specific versions of these genes a person had and how well they responded to natalizumab.
Key Findings: A Double Whammy?
The results revealed some interesting trends:
1. While there weren't significant differences in the individual NQO1 or GSTP1 gene variations between responders and non-responders when looked at separately, there was a noticeable tendency for responders to have the "wild type" (more active) version of the NQO1 gene.
2. The most striking finding emerged when the researchers looked at the combined effect of both gene polymorphisms. They found a significantly higher frequency of individuals with mutant versions (less active forms) of both the NQO1 and GSTP1 genes in the non-responder group compared to the responders. In fact, almost half (46.7%) of the non-responders carried mutant forms of both genes, compared to only 23.1% of the responders.
3. This suggests that patients who have the more active versions of at least one of these detoxification genes (either NQO1 or GSTP1) might experience a better clinical outcome with natalizumab therapy.
What Does This Mean for MS Treatment?
These findings hint at a possible link between the body's ability to combat oxidative stress and the effectiveness of natalizumab. The researchers propose that natalizumab might exert some of its protective effects by reducing oxidative damage in MS patients. If a patient's natural antioxidant defenses are already compromised due to less active forms of NQO1 and GSTP1, they might not benefit as much from natalizumab's potential antioxidant effects.
This research opens up exciting possibilities for understanding the mechanisms behind natalizumab's action and for potentially predicting treatment response. While natalizumab primarily works by blocking immune cell entry into the brain, this study suggests that its impact on oxidative stress might also be important.
Important Considerations and Future Directions
The researchers acknowledge that this is a single-center study and that they didn't directly measure antioxidant levels in the patients. Therefore, further research with larger groups of patients and direct measurements of oxidative stress markers is needed to confirm these findings. Additionally, the study didn't analyze the relationship between the number of natalizumab infusions and clinical response.
Nevertheless, this study provides a valuable indication that our genetic makeup, specifically genes involved in managing oxidative stress, could play a role in how well we respond to natalizumab treatment for MS. This knowledge could potentially contribute to a more personalized approach to MS treatment in the future, helping doctors better predict which patients are most likely to benefit from natalizumab therapy. It also highlights the ongoing efforts to unravel the complex mechanisms of MS and identify factors that influence treatment outcomes.
In conclusion, this study suggests that having less active forms of both the NQO1 and GSTP1 detoxification enzymes may be associated with a poorer response to natalizumab treatment in individuals with MS. This points towards a potential role for antioxidant mechanisms in natalizumab's effectiveness and underscores the importance of further research in this area.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Alexoudi, A., Zachaki, S., Stavropoulou, C., Gavrili, S., Spiliopoulou, C., Papadodima, S., ... & Sambani, C. (2016). Possible implication of GSTP1 and NQO1 polymorphisms on natalizumab response in multiple sclerosis. Annals of Clinical & Laboratory Science, 46(6), 586-591.
