Gene Therapy: A Promising Approach for The Epilepsies? - José M Serratosa, Hospital Universitario Fundación Jiménez Díaz, Spain
What does the future for epilepsy treatments hold?! Epileptologist José M Serratosa shares his predictions for epilepsy gene therapies; highlighting the importance of addressing all symptoms - including cognitive, motor, and psychiatric - as well as the seizures. Jose explains the role of viral vectors and how they may save people!
This is part 1 of 2 with José - in part 2, the conversation goes into the challenges of research clinical trials for these therapies; from basic, to pre-clinical, to clinical!
Reported by Torie Robinson | Edited and produced by Carrot Cruncher Media.
Podcast
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00:00 José M Serratosa
"We believe one injection in your life is enough to, you know, control the disease."00:11 Torie Robinson
Fellow homo sapiens! Welcome back to, or welcome to: Epilepsy Sparks Insights.
Now, not everyone realises it, but as our guest this week, neurologist and epileptologist José Serratosa explains, seizures are only one symptom of an epilepsy (and sometimes not the "worst" symptom!) and he shall share how to him, the most exciting potential for us when it comes to improving the lives of people with (and families affected by)the epilepsies, is gene therapy!
Please don’t forget to like, comment and subscribe to the channel if you haven’t already, so that we can educate way more people affected by the epilepsies around the world.00:49 José M Serratosa
Hi Torie, it's a pleasure to be in your podcast. Well, I am a neurologist and epileptologist with a special interest in genetics, but, my interest in genetics is focused especially in doing something useful for the patients after we find the abnormal mutations or the gene that is involved in a special or specific type of epilepsy. So, I work in a university hospital here in Madrid in the epilepsy unit (that's the clinical part of the work) and in a research lab where we do new therapies, we study new therapies for a special, specific type of epilepsy.01:42 Torie Robinson Robinson
Why did you decide to focus on these epilepsies?01:45 José M Serratosa
60 to 70 percent of the epilepsies are well controlled and most patients have not many problems in life, but the rest of the epilepsies are really a problem for the patients - and the genetic epilepsies are especially a problem because they usually come together with psychomotor delay and cognitive problems, motor problems, et cetera. So, some even die, some patients even die because of the epilepsy and the whole clinical picture. So, I thought it would be, you know, more useful to try to solve these epilepsies and help the patients with effective treatments.02:34 Torie Robinson
Yeah, often I think they're kind of abandoned, especially if there isn't a specialist around and people might say “Okay, I don't know what I'm doing. I'll put them on this drug and hope.” and let them get on with it.”, yeah, and unfortunately, that still does happen.
So, you showed me before I call this really fancy, I confess I got intellectually (well, to my potential!) intellectually excited, about this presentation titled “Future epilepsy therapies” and mentioning of course, ‘precision medicine’, which is a very important but quite a trendy term. What does the future hold for us when it comes to epilepsy therapies; especially when we're talking about genetic epilepsies?03:13 José M Serratosa
I think we will have more specific treatments that target the specific abnormality and we will also treat not only the epileptic seizures but also the other problems that are associated with epilepsy. This can be cognitive problems, motor problems, psychiatric problems, etc.03:39 Torie Robinson
And that's really important and, well, heartwarming to hear, because… it depends on the individual, of course; but often seizures are seen as just one aspect of what we go through and they might not be of priority for us to improve quality of life.03:58 José M Serratosa
Exactly. In the last, you know, two - three hundred years, the efforts have been directed to treat the seizures. And that's why the new name of the medications is anti-seizure medications because they really treat only the seizures. So, now, what we want to treat is the whole picture of the epilepsy. And for that we need to not only treat the seizures, you know, with non-specific drugs, but to treat the whole bunch of symptoms that are coming together with the seizures. So that's what we can do with the... we may be able to do with the new therapies04:44 Torie Robinson
I love it. And so... and I am reading out a list to be fair, just so everyone knows(!), but, so, we're looking at gene therapy, oh… how do I pronounce it? So anti sense, olig, olig…oh, I can't say it right!. Oligonucleotides! And…05:01 José M Serratosa
Right!05:02 Torie Robinson
…antibody enzyme, enzyme replacement, drug repositioning and small molecules. Could you give us a little oversight of that, please (these approaches)?05:11 José M Serratosa
Okay, the most exciting in my view is gene therapy for the many, many, probably hundreds of genetic epilepsies that are around and have been discovered because what we can do is usually replace a gene that is abnormal (that has a mutation) with a normal gene. So, it's maybe the most simple way of thinking if you have a, let's say, a “broken” gene let's put in a “normal” gene and hopefully [if] we do this early enough we can prevent the disease and in some cases that have [already] evolved we can prevent the disease from progressing. So, this is gene replacement therapy which can be very useful for recessive diseases where there is no gene working. Both copies of the gene are abnormal.
For other genetic diseases, we have other, as you said, other forms of treating that may be more useful. But I would also like to mention gene therapy for focal epilepsies. And there is a group in London at UCL that is injecting genes that code for ion channels (of different types) in the epileptic focus, that can change the microenvironment of the brain (in the focus) and control [in] this way the epileptic seizures. So, instead of taking out a piece of the brain - which is maybe not very precise or very refined - we may be able in the future to inject a gene: to just to inject a viral vector with a gene in the focus (so that wouldn't make any deficit or problems as you can have with resections) and it may be able to control the seizures. So that's being developed and it works in animal models.07:49 Torie Robinson
That is so cool because whenever I think of gene therapy, I always think of generalised epilepsies. And so, for it to be potentially applicable to people who have a focal epilepsy, that's a really big deal.08:03 José M Serratosa
Exactly. So, that may be as easy as going to the hospital and having an injection in part of the brain where your focus is and hopefully you could be cured.08:18 Torie Robinson
Where would we get the matter that is injected? So the gene. Is it something that's put together that’s sourced originally from the patient's own DNA or how does that work?08:30 José M Serratosa
Well, this is a construct that is, prepared or fabricated in a facility where a special type of virus is processed and it's basically an artificial virus where we can insert the gene that we want to be expressed.08:56 Torie Robinson
So, it's like… it's a “useful” virus rather than saying, you know… I don’t know - there are many “non-useful” viruses - and it kind of “infects”, is that the right word? But basically, passes on the message to the genes surrounding it. Is that right?09:12 José M Serratosa
Yeah. Well, these are actually, we call them viral vectors. They are not really viruses. So, what the best vectors do is just float in the cell, inside the cell and produce the protein that is not being produced by the abnormal gene. They don't integrate into the normal DNA…09:42 Torie Robinson
Okay.09:43 José M Serratosa
…so they don't go and, you know insert…09:46 Torie Robinson
Change everything.09:48 José M Serratosa (10:46)
Exactly. Because if that happens you may break a normal gene and make things worse(!). So they just float in the cytoplasm; they don't reproduce, they don't (hopefully) produce an immune reaction (but they may. That's the main problem/one of the main problems). So, they are just like vectors (that's why we call them vectors) that carry the gene into the cell without producing any abnormality.10:22 Torie Robinson
And so, you say this can be (sic) an autoimmune response - is that because it's identified as being a foreign body?10:27 José M Serratosa
Yeah.10:28 Torie Robinson
And so we have to figure out a way for that not to happen. Is that where we are?10:32 José M Serratosa
Exactly. That's one of the problems some vectors may have, but the good thing about gene therapy is that we believe one injection in your life is enough to, you know, control the disease.10:53 Torie Robinson
That would be life-changing for millions of people. And I'm sure, like, I have, gosh, I don't know numbers, but the investment required for the research into this is staggering. But, once, like, this could roll out, just a simple injection for people to prevent their epilepsy from occurring, the seizures and the morbidities that go with it, just…thinking how that could alter a person's life!11:21 Torie Robinson
Thank you so much to Jose - for sharing with us such empathy when it comes to patient and family experiences with the epilepsies, plus his own hope and excitement when it comes to gene therapies!
Do check out more about Jose and his work on the website torierobinson.com (where you can also access the podcast, video, and transcription of this episode), and if you haven’t already, don’t forget to like, comment, and subscribe to the channel, share this episode with your friends/colleagues/family members, whoever (!) and, see you next week! -
José M. Serratosa is a neurologist specialising in epilepsy in Madrid. He obtained his Doctorate in Medicine and Surgery from the Autonomous University of Madrid . After completing his residency at the Neurology Service of the Puerta de Hierro Clinic , he trained in epilepsy at the University of California, Los Angeles (UCLA). Subsequently, he was appointed Associate Researcher in the Department of Neurology at the UCLA School of Medicine.
José has a strong scientific interest in the characterisation of epileptic seizures, surgical treatment of epilepsies , genetics of epilepsies, progressive myoclonic epilepsies (including Lafora disease), neuroimaging studies in epilepsies and mechanisms of resistance to anti-seizure medications and the development of adverse effects to them.
José has published numerous articles in international journals and has contributed chapters to specialised books. He has also served as Associate Editor of the journal Epilepsia , published by the International League Against Epilepsy , and is on the editorial board of the journals Seizure and Epilepsy Research . He is also a member of the Genetics Commission of the International League Against Epilepsy.
In 1995, José joined the Neurology Service of the Jiménez Díaz Foundation , where he established the Epilepsy Unit and continues to carry out his clinical, teaching and research work. Since 1995 he has directed the Epilepsy Genetics Neurology Laboratory.José discovered the locus of the first gene for Lafora Disease and was the co-discoverer of the EPM2A gene; one of the two genes where mutations are found in Lafora Disease.
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