Ep. 206: Genetics in ALS and frontotemporal dementia – from pathophysiology to treatment

00:00:00: Welcome to EANcast, your weekly source for education research and updates from the European Academy of Neurology.

00:00:14: Hello!

00:00:15: And welcome to Eancast Weekly Neurology.

00:00:17: My name is Klaudia Sanciova.

00:00:19: I'm a neurologist and clinical neurophysiologist trainee at Hospital Garcia de Oroca Portugal Also co-share of ALS and front on temple dementia EAN scientific panel.

00:00:29: This month topic is ALS and from the tempered dementia.

00:00:32: And in today's episode, we'll talk about genetics and ALs and FTD.

00:00:37: My guest today is Professor Andrea Calvo.

00:00:39: Prof.

00:00:40: Andrea Calville is an associate professor of neurology at Rituali V Montaccini Department of Neuroscience at University of Turin Italy with research interests in motor neon disease including phenotyping neuroepidiology, neuro-imaging cognition, genetics and palliative care.

00:00:57: Welcome Professor Andrea Calvo and thank you for joining us today.

00:01:01: Thank You very much for the invitation.

00:01:03: My first question to your professor is so when we think about ALS and FTD, how many of these diseases can be attributed to genetics?

00:01:14: The spectrum that we call an ALS-FFTD spectrum is a paradigm that will learn particularly from genetic background.

00:01:24: When we discover the CNA in August expansion, and also when we describe the phenotypes among TAR-DVP mutations on fast mutation.

00:01:35: We learn that in front of them they are facing a very particular spectrum which goes from pure FTD to pure ALS.

00:01:54: between gene and environment.

00:01:58: And we have all in this spectrum a lot of particular characteristics that are related to the disinteraction, We also say that ten to fifteen percent of ALS-PD cases associated with monogenic mutations thought that they are responsible for the disease.

00:02:28: But there is a lot of problems, I think we can mention after in this podcast.

00:02:36: Thank you!

00:02:37: So regarding research how do you think genetic research has helped us to understand underlying mechanisms both ALS and FTD petrophysiology?

00:02:49: The first Mendelian gene discovered there was the superosid dismutase I, Gene SOD-I.

00:02:56: And we had the luck to develop very rapidly in animal models.

00:03:03: from this model.

00:03:05: We learned a lot of things and history of the researcher particularly in the SOD.

00:03:13: one arrives today.

00:03:15: it's that therapy...a very specific therapy that I will mention after.

00:03:23: So, different models are ongoing also for SOD-One in using other type of model such as IPSC cells or organoids and we hope the future organos would be very useful.

00:03:43: It's very difficult to build an efficacious and efficient model using TAR-VDP mutation, because we have different models that are not representing a very well the disease or they're not useful in research.

00:04:02: We are now trying to build a senile model with something quite good in fast.

00:04:10: The information that's coming from the genetic models changed dramatically our knowledge about ALSFT spectrum.

00:04:24: Thank you, and so definitely genetics has a big role in this spectrum.

00:04:31: And regarding our clinical practice how do we think when should be considered genetic testing for patients?

00:04:37: In all cases, in specific cases what is your idea?

00:04:43: Yes nowadays the genetic counseling has a key point of care at ALS center because we have some therapies.

00:04:53: We also have specific target engagement trials that are related to specific mutations so you can learn how a pathetic presence of imitation.

00:05:10: We learn how to manage this type of counseling, but we in for example Torino do it with this procedure with the geneticists.

00:05:22: so we have a multidisciplinary counseling team together also with a psychologist because the impact of a mutation is so important for patients and relatives, family or caregivers.

00:05:40: The problem in genetic counseling is the definition of homogeneity which is very crucial point And also the fact that in presence specific mutations, pathogenic we have to deal with the low penetrance of most of this mutation, in particular for TAR-VDP but also for SOD-I or PAS and also for C-NAIN-ORF, the penetration is not an under percent.

00:06:15: So you have to learn how to communicate their role over these mutations persons with ALS, and more important for the relatives because we have to plan eventually follow-up or a presymptomatic follow up for carriers of this type of location.

00:06:42: So genetic counseling has became crucial in daily point over our care in ALS centers.

00:06:53: Yes!

00:06:54: And my idea is that A couple years ago, we only tested the patients who had family history of motor neuron disease or FTD.

00:07:02: And now with tests... We tend to test everyone wants to be tested.

00:07:07: so definitely the paradigm is changing right?

00:07:11: Yeah!

00:07:11: The point is that if you have to offer the genetic testing for all the patients it depends then on health care system different countries aviability of the genetic labs.

00:07:27: but we have to offer the genetic testing for all patients.

00:07:32: And I think you already tackled a little bit on this, what do you think are the biggest challenges when interpreting the genetic results?

00:07:42: What are the biggest challenges when interpreting genetic results?

00:07:45: The big challenge is that we're in a next generation era.

00:07:53: Okay, and now... We have long-term sequencing of the NGS sequencing, the NGS sequences for clinical practice had been performed with a short reading.

00:08:13: Now we have long-reading sequencing.

00:08:16: so now finding lots of variants more than before and learn how to manage the past variant without sense or significance.

00:08:33: It's a challenge, so the communication of the role in this uncertain variance is very difficult.

00:08:42: There are not genetic guidelines for these issues but probably we have to invest time and science.

00:08:56: The interpretation also is different, the challenge for the penetrant.

00:09:05: So how to communicate a presence of a mutation in a pedigree?

00:09:11: And also we can have a playotropy characteristic of these mutations.

00:09:21: We have lots of different phenotypes in the same pedigrees and family carrying the same mutations.

00:09:29: persons that are affected from extra-pyramidal, pyramidal, a pure ALS cognitive disorder movement disorders and so on.

00:09:39: This is another important point in this challenge.

00:09:43: we have to describe all the pedigrees and all of cases in order to find with right way communicate our findings in genetic testing.

00:09:58: So now coming from diagnosis to treatment.

00:10:02: We've already spoke a little bit about the treatment, but how is genetics changing the landscape of treatments mainly in ALS and also FTD?

00:10:17: Yes now we have lots of targets.

00:10:21: The problem is that in neurodegeneric disorders engage with the gain on function mutation.

00:10:34: So when we have a loss of function, it's very difficult to be able to impact disease modifying treatments.

00:10:43: if that we ever again all functions such as SOD one rotation We can try to impact in the course of the diseases trying to block the transcription or directly the gene and DNA sequence.

00:11:02: So, real effect of genetic research in ALS-RTD is that they showed us a lot targets so we are now able to try to impact blocking on modifying these targets.

00:11:22: And then we found some therapies.

00:11:28: treatments are ongoing in clinical trials.

00:11:32: And can you talk us a little bit about the experience?

00:11:37: Yes, for example, for SOTY-I in this very nice research history that starts in nineteen ninety three discovering the mutation we finally arrived at any an efficacious treatment with the enoligo nucleotide and anti-sense nucleonucleotides called Tofersen.

00:12:00: This is a enoligoneucleothide that's able to block the mRNA, which demonstrates in phase one, phase three travel falls down and also the level of neurofilaments.

00:12:22: And, we have an open label extended evaluation in important clinical effect on this compound.

00:12:33: There are other types of attempts using also ASOS for example from FAS.

00:12:41: there you can go with a phase one phase three trial confident, and we hope that it can have an effect because the hypothesis is that there's a gain of function mechanism.

00:13:01: We failed in some attempts for example from Sina in Orca or with trying to interfere with Atex II expansion expansion risk factor and prognosis factor that is so important.

00:13:23: So some successful attempts, but the problem we are now in right way on the right road waiting also for real gene therapy attempt to block and modify directing the DNA, the mutation of some of the genes related associated with the disease.

00:13:56: What do you think about the C-ni-NORF?

00:13:58: what are the challenges?

00:13:59: because this is most frequent gene involved both ALS and FTD.

00:14:03: but clinical trials... and not being successful.

00:14:06: The problem of CNA in ORF is that we have both the mechanism, loss-of-function and gain-of function probably so you had to manage it with this very complex mechanisms.

00:14:22: many labs are now trying differentiate the intervention in part of gain and avoid loss.

00:14:36: That's another problem which is the ability to build a reliable disease model, it's very difficult.

00:14:50: There are a lot of preclinical attempts to build ASOS, different obviously from the ones that failed two years ago.

00:15:02: So I think that Cina-NORPH is also very complex type for mutation because it's an azanucleotide expansion.

00:15:14: so... we have patients with an incredible number of expansions and patient that are related to a very, a numbered below than one hundred expansion of this sequence.

00:15:28: So there's an heterogeneity between the C-ninof mutation which is another important problem in finding the... because choose a treatment in these type of patients And also the pleiotropy, so they... The pedigrees and carriers can develop just an FTD or just only an ALS purer, a ALS phenotype.

00:15:57: Or very complex clinical manifestation with lots of systems involved.

00:16:04: So that's another point

00:16:07: Definitely!

00:16:08: Very complex topic Also very exciting

00:16:12: one.

00:16:12: I think we are in the right way now And I think, and i hope that you find something better than Tophersen.

00:16:20: The Topherson represent a revolutionary moment in AIS research.

00:16:28: Definitely yes!

00:16:30: We hope for the best... In future.

00:16:33: So thank-you so much Professor Andrea Calvo.

00:16:35: Let me just give some take home messages For the listeners.

00:16:39: Today we spoke little bit about genetics of ALS & FTD their role in pathophysiology and diagnosis, treatment.

00:16:48: We know for sure now that ALS and FTD are part of the same disease spectrum and they share a genetic basis.

00:16:57: And there's lots of key genes including of course CNRF-II but also others like SOD-I, FOSS and many other.

00:17:07: Genetics has provided crucial insights into disease pathophyseology.

00:17:12: So we know there are many mechanisms including RNA metabolism dysfunction, protein ingrupation, autophagy, neuroinflammations which are relevant across both familial and sporadic diseases.

00:17:29: And also genetic testing is becoming an essential component of clinical care not just for diagnosis, but also for prognostication.

00:17:40: For family counseling as Professor Andrea Calvo mentioned and for the eligibility to...for clinical trials and access emerging gene targeted therapies.

00:17:52: However there are many challenges regarding interpretation of genetic results And of course ethical concentration that we have keep in mind.

00:18:01: Also genetics is driving us the transition towards precision medicine in ALS and FTD with a development of gene targeted therapies, and also biomarker-guided patient certification.

00:18:15: And first for SOD-I associated ALS is good example of that.

00:18:20: so we are creating new therapeutic opportunities bringing genetic discoveries closer to clinical application.

00:18:29: While many challenges remain, the integration of genetics into research and clinical practice is reshaping how we diagnose our treats.

00:18:37: And now to... We understand ALS and FTD in offering a renewed hope for our patients' and their families.

00:18:46: Thank you again!

00:18:48: To Professor Calvo for joining us today and thank you to all listeners who are tuning-in to YANcast Weekly Nology.

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