Beatrice de Gea/The New York Times

March 27, 2022

Weill Scientists Reach New Heights With Multiple Sclerosis Drug Treatment

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On Feb. 8, a new study on the multiple sclerosis drug siponimod conducted by researchers from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center was published in Nature Communications. The study analyzed the drug’s shape and interactions in the body, allowing researchers to understand how to lessen the drug’s side effects, such as heart and liver problems, during treatment for MS patients. 

Multiple sclerosis is an autoimmune and neurodegenerative disorder, caused by the body’s own immune cells attacking its nerve cells. Immune cells attack the myelin sheath surrounding nerve cells, leading to the gradual degradation of the nervous system. Because the myelin sheath plays a role in communication between nerve cells, MS creates communication issues between the brain and the rest of the body. As a result, permanent damage to the nervous system occurs, and the body experiences various symptoms, ranging from numbness in limbs, shock sensations in the neck, a lack of coordination and vision problems. 

According to Prof. Xin-Yun Huang, physiology and biophysics, senior co-author of the study, the causes of autoimmune diseases like MS are still unknown. “We just don’t understand what really causes multiple sclerosis [and] why suddenly our immune cells attack our neurons because it’s not clear,” Huang said. 

However, while MS itself is incurable, drugs developed for MS treat patients by relieving their symptoms. 

MS drugs are designed to target S1P1, a member of the S1P receptor family. S1P1 is especially important in white blood cell movement in the immune system—a crucial aspect behind the cause of MS. Drugs binding to S1P1 thus inhibit immune system functioning, preventing it from damaging the body’s nerves and reducing MS symptoms. “S1P is an active lipid that is produced and secreted by red blood cells and platelets in our body,” Huang said. “The way [S1P] works in our body is by acting on five S1P receptors: S1P1, 2, 3, 4 and 5.”

Although first-generation MS drugs were able to bind to the S1P1 receptor, they also bound to S1P2, 3, 4 and 5, resulting in serious side effects. For example, the binding of the drug to the S1P3 receptor results in heart problems like bradycardia and atrioventricular block, as S1P3 performs functions related to the heart. 

Second-generation drugs such as siponimod were developed to prevent binding to S1P2, 3 and 4 receptors, but researchers still faced challenges when it was still bound to S1P5 in addition to the targeted S1P1 receptor. 

To determine why siponimod bonded only to S1P1 and S1P5 receptors, Huang and his team examined its structure and interactions with two very similarly-structured lipids—S1P and LPA. According to Huang, to understand how receptors distinguish S1P from LPA, one should think of  the lipids as a key and the receptors a lock. Because keys have very distinct shapes, the locks corresponding to each key must also have a specific shape such that only one key will be able to fit into the lock. 

Huang concluded through the study that siponimod only binds to S1P1 and S1P5 receptors due to the compatibility of the drug’s shape and the shape of the receptors. On the other hand, the drug does not fit into S1P2, 3 and 4 receptors, as the receptors’ shapes happen to be slightly different from S1P1 and S1P5. 

Utilizing this information, researchers can further develop MS drug treatments by adding parts that bind to these extra binding sites in S1P1, making them able to bind only to the target receptor, S1P1. 

Although it may now be possible to make an MS drug specific to S1P1, Huang shared that this may not completely remove all side effects of MS drugs. 

“As you can imagine, since the S1P1 receptor is so critical for lymphocyte trafficking, it’s a normal part of our body because the lymphocytes need to attack the foreign pathogens,” Huang said. “So you cannot use the drug for too long because [it will be] very easy to get infections.” 

Because an MS drug stops the immune system from attacking nerve cells by inhibiting it, the drug shuts down other functions of the immune system as well. However, with proper management on drug usage and dosage for patients, an S1P1-specific MS drug would have only the side effects of a weakened immune system if it were to not bind to other S1P receptors.  

According to Dr. Huang, the study of siponimod’s structure and interaction with the body can be applied to the further development of new generation MS drugs, in hopes that a disease with no cure can be treated more and more effectively. 

Dr. Huang also stated that his research can be applied to drugs for other autoimmune diseases, as it focuses on the S1P1 receptor and its function in the immune system, according to Huang. “S1P1 actually [regulates] a lot of [functions], for example, angiogenesis in our blood vessel formation and heart rate modulation, so it can be used for other diseases as well,” Huang said. “And so people are trying to test that in the clinics, in addition to MS.”

Ultimately, the MS drug study will provide patients struggling with chronic illnesses with newly developed treatments with less painful outcomes and more effective care.