Multiple sclerosis, an autoimmune disorder, is one of the more prevalent rare diseases worldwide. An estimated 2.3 million people are living with multiple sclerosis, whose cause remains unknown.

Francisco J. Quintana, Ph.D., professor of neurology at Harvard Medical School and the Ann Romney Center for Neurologic Diseases at Brigham & Women’s Hospital, is researching the role immune system cell signaling pathways play in the progression of multiple sclerosis and other neurodegenerative diseases.

His exploration of these pathways has yielded targets for potential therapeutic intervention in treatment of secondary progressive multiple sclerosis, which is a primary focus of his research, and also in other neurodegenerative diseases. Progressive multiple sclerosis is a later, more debilitating stage of the relapsing and remitting form of the disease that affects most multiple sclerosis patients. 

Another unique element of Quintana’s research is the identification of environmental factors, such as herbicides, that can affect central nervous system inflammation and neurodegeneration involved not only in multiple sclerosis, but also Alzheimer’s and Parkinson’s diseases.

“When we look into any immunologic or neurologic diseases it is very clear it’s not only genes that drive their development, but also environmental factors like exposure to chemicals,” Quintana explained.

As part of an exclusive series spotlighting rare diseases and the challenges of developing new drugs for these illnesses, WuXi AppTec Communications spoke with Quintana about his Harvard laboratory’s research efforts.

Quintana earned his undergraduate degree from the University of Buenos Aires and his doctorate in immunology from the Weizmann Institute of Science. In addition to his post as professor at Harvard Medical School, he is an associate member of the Broad Institute at Harvard and MIT, and he is the president-elect of the International Society of Neuroimmunology.

WuXi AppTec: How does researching new drugs for rare diseases differ from research into more common diseases?

Francisco Quintana: There are two main differences. On one hand you have a more limited number of clinical samples you can access in order to identify mechanisms of disease pathogenesis. That ultimately makes it more difficult for you in terms of the things you can access from the scientific community. Those samples are more precious, so not everyone has access to them.

The second point, which I think plays a critical role, is if you are working with a rare disease then you probably have fewer patients available on which to test your drug candidate.

WuXi AppTec: How much progress has been made in multiple sclerosis drug research and development over the 20 years?

Francisco Quintana: There have been significant advances, but those have been limited to a very specific phase of the disease. The reason is that multiple sclerosis initially presents in most patients as the relapsing, remitting form of the disease, in which patients endure a neurologic attack and then they will do better. This is a cycle that can go on for years.

However, eventually most patients transition into progressive multiple sclerosis in which they accumulate a neurologic disability without recovering from attacks. And that’s important because over the past 25 years we have developed, as a community, multiple drugs that target and benefit patients affected by relapsing-remitting multiple sclerosis, yet there is still a huge unmet clinical need for drugs that target the progressive phases of the disease.

WuXi AppTec: How did you get involved in research on multiple sclerosis? Why did you choose this particular disease?

Francisco Quintana: I think it has to do with a history of neurologic disease in my family together with my interest in immune and autoimmune diseases.

WuXi AppTec: What is the focus of your research?

Francisco Quintana: Basically we are interested in mechanisms of regulating immune pathways that regulate T-cell responses. As part of those studies we have identified multiple signaling pathways involved in that, including the aryl hydrocarbon receptor (AHR) for which we developed a nanoparticle that can therapeutically target the receptor. The nanoparticle has been developed as novel therapies targeting central nervous system (CNS) autoimmunity and also autoimmunity targeting other tissues besides the CNS.

In addition, we have also identified other pathways that play the same role in controlling effector T cell responses. One of the most exciting things we are doing is being very focused on trying to identify mechanisms that control inflammation in the CNS driven by resident cells, such as microglia and astrocytes. That’s important because the mechanisms that control those cells are thought to drive inflammation and neurodegeneration in progressive phases of multiple sclerosis and other neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.

We believe that by identifying what regulates and controls astrocytes and microglia we can identify therapies for the secondary progressive stage of multiple sclerosis and for other neurodegenerative diseases.

As part of our studies we also have identified pathways by which the environment, the gut flora, metabolism, microglia and T cells control astrocytes and microglia for inflammatory responses.

WuXi AppTec: Have you licensed any of your research for clinical development?

Francisco Quintana: We have established a start-up company from our laboratory which is focused on the development of nanomedicine for antigen specific T cell modulation, and that was established initially in partnership with Pfizer. Pfizer already has in-licensed one of our products, which is targeted at Type 1 diabetes.

We’re in the process of partnering with other companies. We have developed products that will be useful for T cell specific modulation in other diseases, including celiac disease and multiple sclerosis.

In addition, we have novel inventions/targets that are available for licensing.

WuXi AppTec: What kind of environmental factors are you investigating in relation to inflammatory responses?

Francisco Quintana: When we look into any immunologic or neurologic disease, it is very clear it’s not only genes that drive their development, but also environmental factors like exposure to chemicals in the environment, which go to the gut microbiome. That can affect the development of autoimmune disease and neurologic disease in individuals who have specific genetic backgrounds.

What my laboratory has done is to identify many of these factors and use these environmental chemicals as probes to identify novel mechanisms that regulate CNS inflammation. That has also led us to identify novel pathways that regulate CNS inflammation, which in turn has led to the identification of potential novel approaches and therapeutic targets.

WuXi AppTec: What specific environmental chemicals have you identified?

Francisco Quintana: We identified an important role for herbicides in triggering CNS inflammation, and that led us to identify a role for a specific receptor as part of the physiological control of inflammation. That’s important because if we know the receptors then we can use small molecules to modulate their functions.

WuXi AppTec: What major challenges do you face in bringing new drugs to multiple sclerosis patients?

Francisco Quintana: I would say there are two types of challenges associated with the two types of drugs you might want to develop.

For drugs targeting the relapsing and remitting phase of the disease, the challenge is that there are many other drugs out there that seem to be doing quite well. So your new drug has to do extremely well side by side with other drugs, and getting enough patients to test it would be one big challenge.

The second challenge involves developing drugs for secondary progressive multiple sclerosis; at that stage the disease manifests differently. At this stage, you do not detect well-defined attacks; instead the disease is driven by chronic, progressive neurodegeneration. The outcomes you should focus on at this progressive stage probably are not going to be classic multiple sclerosis disease activity in terms of attacks. The outcomes actually are more MRI (magnetic resonance imaging) based markers and other outcomes. That is a different type of clinical trial, and there you have to start thinking about what it is you are going to specifically measure.

WuXi AppTec: What advice would you give drug companies in developing new drugs for multiple sclerosis and other rare diseases?

Francisco Quintana: For progressive multiple sclerosis, we should develop drugs that target CNS resident cells – astrocytes and microglia – and that means we need to have more basic research and closer interactions with basic researchers to find what are the candidate drugs that target intervention with those cells. That would be my first piece of advice.

Then this is more of an open question: how and where would we be able to even analyze the efficacy of drugs useful for the progressive phase of the disease?

WuXi AppTec: In 10 years, can we get to FDA approval of 100 new drugs per year at half of today’s drug development costs? If not, what are the impediments to reaching this goal?

Francisco Quintana: It seems new models of clinical trial design might optimize our ability to increase the rate of new drug approvals; I think we have to come up with different outcomes, at least for progressive multiple sclerosis.

WuXi AppTec: Overall, do you see our current approaches to tackling diseases as incremental improvements or are we getting more and more transformative?

Francisco Quintana: It’s all driven by the science. In some diseases we are studying new paradigms as in multiple sclerosis, where we are starting to study the role of CNS resident cells in inflammation. That no doubt will guide new drug discovery. The question is will the same apply to many other diseases.

WuXi AppTec: What technological breakthroughs might be game-changing in the next five years? 

Francisco Quintana: One of those breakthroughs is probably the use of single cell technologies in order to characterize patient samples and mechanisms of disease pathogenesis.

The other thing I would say is probably the use of CRISPR approaches as a way of quickly modelling in animal experimental systems some of the things we detect in patients so we can understand mechanisms of disease pathogenesis and identify candidate targets for therapeutic intervention.

Those two would be the ones I think would make a significant contribution.