Identifying Causative Somatic Mutations in Mesial Temporal Lobe Epilepsy May Open the Door to Targeted Therapies

Sattar Khoshkhoo, MD

This is the second part of an interview with Sattar Khoshkhoo, MD. For the first part, click here.

"I think the main takeaway is that we need to rethink everything."

Epilepsy is one of the most extensively studied diseases with its documentation stretching back to ancient times. Despite this, the cause behind mesial temporal lobe epilepsy (MTLE), the most common form in adults, remains elusive.

For the past 6 years, Sattar Khoshkhoo, MD, the founding director of the Epilepsy Genetics Clinic at Brigham and Women's Hospital, and his colleagues have been investigating the potential of a genetic basis for MTLE with the use of patient tissue samples. Khoshkhoo recently presented their findings at the 148th Annual Meeting of the American Neurological Association, held September 9-12, 2023, in Philadelphia, Pennsylvania.

In an interview with CGTLive™ at the conference, Khoshkhoo discussed the big picture implications of their findings, which implicated somatic mutations in the RasMAP Kinase pathway as potentially causative of MTLE. He noted that if these findings are verified with additional experimental research, it may call for epilepsy experts to rethink their understanding of the disease. Khoshkhoo also spoke on the potential of gene therapy and other types of targeted therapies in MTLE.

CGTLive: What are the main implications that the healthcare community should take away from the findings you presented at ANA 2023?

Sattar Khoshkhoo, MD: I think the main takeaway is that we need to rethink everything. MTLE happens to be actually one of the most studied diseases there is because of the fascination going back thousands of years of even ancient doctors with epilepsy. It's been very extensively studied and there is a massive body of research; a lot of good work that has been done over the past couple of decades, all under the assumption that there is no genetic predisposition for this disease. We're still working on establishing that causality and causation, but should it be truly established through more rigorous experimental work, as well, then we are kind of operating from scratch.

I don't think that work that has been done up to now is necessarily invalid because epilepsy is a very complex disease of brain networks. So, it's possible that these variants are involved in that initial process of epileptogenesis, but there is a much larger brain network that is involved that eventually becomes affected. I think that focus on networks, and thinking about epilepsy in that way, is still very valid. But thinking of that initial inciting event as being actually a genetic one I think is really relevant because all of a sudden, we have a significant biomarker that can not only help us [in treating] epilepsy the way we do it now, but also can help us think about these patients as potentially individuals who could benefit from targeted therapies. If you have a drug that specifically targets the underlying gene variant that they have, then there is a possibility for human disease modification in the field, which currently is not available short of a major surgical procedure.

Were there any challenges or limitations in your study, or any areas of interest you’ve identified for future research?

I think one of the main challenges starting this about 6 years ago and getting to this point now is tissue. Really, for us to be able to make informed conclusions about the general epilepsy population and identify relevant clinical information that could be used to hopefully stratify patients who are more likely to have genetic variance causing their epilepsy, having access to a large number of patients, and many centers involved, would be key. That's something I'm hoping to establish in my own lab moving forward—to create a very large collaborative network where we can start looking at thousands of patients and tissue from thousands of patients to really truly understand the molecular underpinnings and how that correlates with our observations in the clinic, MRI, and all the other data points that we have. 

The other challenge is really just going to be technologic advances. I think we are at a very good place right now in terms of the sequencing technologies and the costs of sequencing technologies, but it turns out that many of these somatic variants are present in a very small percentage of cells in the brain. Technologically identifying those somatic variants that are so rare is actually very challenging. I think really pushing that technological envelope forward is going to be key in us also being able to make the diagnosis early, ideally in coming up with noninvasive ways of making the diagnosis prior to someone having surgery, and actually knowing what genetic mutations that they have so that it can even help us know who would benefit from surgery and who would benefit from targeted therapy. I think getting to that point would be the goal.

Can you speak to the potential of gene therapy in MTLE?

I like to think of “gene therapy” as a very broad term. I like to actually refer to it as “targeted therapies”because correcting the specific genetic defect is not going to be realistic for many, many diseases, particularly for MTLE where that population of affected cells is actually very small. But I think being able to design drugs that in a meaningful way modulate either the specific protein product of the gene, the expression of the protein, or some of the other cellular machinery involved would be really revolutionary. It would be something we desperately need in the epilepsy space. A lot of other neurologic diseases are ahead of us in that sense, but I'm really optimistic that we're going to get there.

Is there anything else that you would like to share with our audience?

I think these are very exciting times. As a clinician scientist, I find it truly a privilege to be able to see these patients in the clinic and be able to actually study a very relevant topic to my clinical practice in the lab. I find our findings very surprising, similar to many other epileptologists or clinicians may find, but also, I think, very robust and promising, and I'm fairly certain that it is going to really lead to us rethinking the pathology both from a clinical and scientific perspective.

What I do find particularly intriguing is that because the specific gene pathway that we have found implicated in MTLE, the RasMAP Kinase pathway, has been long studied in the context of other diseases, in particular many cancers, there are already a slew of drugs that are either approved or very close tobeing approved for clinical usage that could easily be repurposed for epilepsy. So I think there is a possibility to actually significantly expedite the timeline of going from discovery to having some kind of a product for the patients simply because of that. I'm quite excited about the possibility of establishing collaborations to make that happen. 

Transcript edited for clarity.

Click here for more coverage of ANA 2023.

REFERENCE
Khoshkhoo S. Somatic variants activating Ras-MAPk signaling cause a spectrum of focal lesions associated with mesial temporal lobe epilepsy. Presented at the 148th Annual Meeting of the American Neurological Association, held September 9-12, 2023, in Philadelphia, Pennsylvania.