Ep. 218: Beyond Symptom Control: Gene Therapy for Rare Neurological Disorders

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

00:00:34: neuroscience department at the Cyprus Institute of Neurology and Genetics in Nicosia-Cyprus.

00:00:41: I am a neurologist and clinician working with neuromuscular, rare neurological disorders.

00:00:48: My research group performs research focusing on innovative cell targeted gene therapies for inherited neuropathies and leukodystrophies And today We are happy to have as guest Professor Jo Eng, who is Senior Research Fellow at the University College London Queen Square Institute of Neurology.

00:01:16: Professor Eng has started her career with an MRC Clinical Research Training Fellowship after completing pediatric neurology training.

00:01:29: Then she went on to complete PhD in gene therapy at UCL and combining her clinical experience of managing children with incurable life, threatening a life limiting neurogenetic disorders without any impactful treatments.

00:01:52: combining with her research experience, she decided to combine this in her career and develop gene therapy for these rare neurogenetic disorders in order to improve the therapeutic landscape of patients with neurological diseases.

00:02:11: So she has developed considerable expertise in translational AV gene therapy.

00:02:21: bring some of these treatments all the way to clinical testing and first in human trials.

00:02:27: So we're very excited to hear her voice, I will start... First off thank you for joining this podcast!

00:02:39: The first question is how did you get involved with the gene therapy field?

00:02:46: Thank you for that really kind introduction.

00:02:51: So as you mentioned, I trained as a pediatric neurologist in the UK.

00:02:57: And... ...I think really what was happening towards the end of my training?

00:03:02: there were genetic revolutions where we started to increasingly diagnose children with rare genetic diseases but still had no treatments and they're so limited for patients who are all very symptomatic and I just really felt the patients deserved more therapies.

00:03:27: So, it was a lucky great Hormone Street that had an opportunity to work with Robert Sertes and Peter Clayton who discovered biomarkers in CSF neurotransmitters and discovered disorders like ADC deficiency, tyrosine hydroxylase deficiency involved in dopamine-transporter deficiency syndrome.

00:03:53: So I was really interested in those disorders, and did my PhD with Manjukuriin and developed a gene therapy for dopamine transporter deficiency And so that's how i got involved.

00:04:06: it Was really as a clinician.

00:04:07: we didn't think had enough treatments For the patients lots of insight into the disease and that we should exploit understanding genetic mechanisms to develop therapies for their patients.

00:04:24: Okay, yeah I think you described a unique position where well-trained clinicians find themselves in facing children and families or parents announced the diagnosis of rare disease and then you don't have treatment to offer.

00:04:45: So I know this can be quite devastating, there's never a stop in their quest for finding treatments.

00:04:54: so that is very inspiring and motivating... ...to do everything possible to make progress.

00:05:03: Why do you think gene therapy is important especially in the field of neurology?

00:05:09: You already described some of these rare diseases, but I think that's true for many other neurological disorders.

00:05:18: That you know we don't have therapies today.

00:05:24: so i think for a rare disorder is where we to an extent understand gene function and often the kind of bile loss or function.

00:05:35: mutating.

00:05:36: gene therapy makes a lot sense And when I started my PhD, they had just done a compassionate trial for ADC deficiency which over the last decade has become licences upstars across Europe.

00:05:55: That is really effective and incredible gene therapy.

00:05:59: so ADC patients normally make no progress in what died by the time there was seven years old the gene therapy for spinal muscular atrophy.

00:06:14: The whole landscape of that disease has completely changed, and these are really key principles of the potential genetic therapies in how we might start to better understand things like dementia complex neurodegenerative diseases Parkinson's disease and apply genetic therapies to these much broader, very difficult disorders where there is really even less than the rare neurological diseases.

00:06:51: I think that's just a huge clinical need to treat neurological disorders And we are really lacking across from pediatrics to adult neurology.

00:07:01: with an ageing population We need to explore so many different avenues.

00:07:09: Yeah, I think you highlighted and first of all the fact that this first successful transformative therapies like Apsdansa and Zolkensma have really changed The course of these disorders but also change their way.

00:07:26: we think about Neurological disease.

00:07:30: And now we get to realize that We can really change things as long the mechanism right and timing right.

00:07:39: The other important aspect is that a lot of these very rare genetic diseases share common mechanisms, cellular pathways even gene dysfunctions with more common neurodegenerative sporadic diseases.

00:08:00: I can think of SMA where you know, it has really changed the way we think about ALS.

00:08:07: About sporadic modern neuron disease and has really motivated a lot of research to develop genetic therapies for ALS And will already have successful therapy For one familiar ALS type.

00:08:22: but I think that whole landscape is changing through this early success stories.

00:08:30: We need more obviously.

00:08:33: So my next question is, can you tell us a little bit more about the successes of gene therapy in your area?

00:08:41: Can You Tell Us A Little Bit More About For Example The Dobamine Transporter Deficiency And How This Was Made Possible To Be A Successful Clinical Therapy.

00:08:56: So, dopamine transporter deficiency is an ultra rare neurotransmitter disease.

00:09:02: It's called by biolake loss of function in the dopamine transporters.

00:09:07: and so it was just... The gene was discovered in two thousand nine by my PhD supervisor Manju Kurian.

00:09:15: And a key to that really where we worked with.

00:09:21: first labs identify the CSF neurotransmitters and develop the biomarker systems.

00:09:28: So when we characterised patients initially, We studied their mutations in vitro and showed that they really had only about five percent transporter function remaining.

00:09:43: And then later on I described another patient cohort with atypical dopamine transporter with much later onset disease.

00:09:52: so they were presenting much milder about ten with head tremor.

00:09:57: So we understood that if you could restore even a little bit of function from five percent to eight percent, you could hugely change potentially the function of these children.

00:10:10: and so we set about developing a gene supplementation therapy soon to restore some residual function.

00:10:20: Initially, quite innovative work where we tested the gene therapy in IPS dopaminergic neuronal models to show that gene supplementation restored function and neuronal survival.

00:10:34: And then move it all into InVivo in the Dopamine-transported knockout mouse model.

00:10:41: We treated mice at two stages as neonatal mice.

00:10:46: so if could ever... diagnose these patients at birth, how effective the treatment would be.

00:10:54: And then also as adult mice.

00:10:57: so if we were treating patients much later in their disease and you're able to show pre-clinical gene therapy efficacy both ages and our IPS model I think this is probably one of the first Gene Therapy studies where they had this crossover within vivo and human IPS your own model of the disease.

00:11:21: And that really helped us push things forwards to late pre-clinical studies and approvals with, you know regulatory support.

00:11:34: so it's...and then we've done some late pre clinical work where we have gone up in GLP level.

00:11:40: manufacturing tests at the vector manufacturer towards clinical trial grade is still effective and potent.

00:11:50: So what has really helped us move this forward is our insight in how to improve dopamine transporter function and knowing having a Really well characterized mouse model And understanding the patient disease.

00:12:07: so we could model our Pre-tinical efficacy on the patient's disease.

00:12:13: We had a very clear biomarker developed at UCL from the patient cerebral spinal fluid that we could model in the mouse model as well.

00:12:23: And also, hand-in-hand being a leading centre that diagnoses the patients.

00:12:30: so all along We've been able to keep their you know leading patient registry.

00:12:36: So all these things have been very unique To this disease being something that we've grown discovering the gene, to modeling in the mass model and being a centre of AV therapy development expertise at ACL.

00:12:55: So all these things is huge collaborative team effort but that has to some extent smoothed away for this being relatively straightforward.

00:13:07: In the background to all of this how we design a gene therapy very much modeled what's in the clinic with Upstazer as well.

00:13:17: So we were able to lean on all kind of non-human primates data and clinical data about upstazers, a very similar disease A, D deficiency.

00:13:31: that has helped us get this into the clinic more quickly.

00:13:35: I think so it is both understanding science, the clinical diseases what's in the field, in a clinic as well that helped.

00:13:46: Okay thank you.

00:13:47: I mean there was very nice description of all the ingredients for success for developing a successful gym therapy because we really need to have this and i think thats also model whatever other successes will hopefully be having in future.

00:14:04: it requires all these things model selection, step-by-step proof of concept good patient cohorts.

00:14:18: you know both the clinical and basic science expertise.

00:14:22: And learning from other therapists.

00:14:25: so I think that's a very clear model for what is successful in therapy development should be.

00:14:33: this brings me then to the other question What do that you have faced or, in general we face in gene therapy developments today.

00:14:46: What are the difficulties and drawbacks?

00:14:57: I think now world has much more experience of Zolgen's my gene therapy.

00:15:03: so the gene therapy for SMA you know, it was approved in twenty seventeen and I believe over three thousand patients have been dosed with Zorgensma.

00:15:16: So there's key things about SMA.

00:15:21: that time is neuron and timely diagnosis And the therapeutic window for Zorgansma Is really a key on how effective and the prognosis of these patients are.

00:15:33: so... I think in the

00:15:37: U.S.,

00:15:38: an SMA diagnosis is treated like a genetic emergency, so they are fortunate to have newborn screening and there's significant pressure to dose babies within few months of age.

00:15:54: In the UK under the NHS we don't have national newborn screenings.

00:16:00: So we had newborn screening in Scotland because it was devolved And then only recently has newborn screening been approved in England.

00:16:12: So this landscape is changing, I think... In France they have new born screening for SMA and then decide which genetic therapy the newborn will have.

00:16:27: so it's about diagnosing patients within an optimal therapeutic window.

00:16:33: that is a key constraint I think, for any of these disorders because you're trying to restore cellular neuronal function with gene expression.

00:16:46: So essentially your outcome will be better if the cellular status is not neurodegenerated.

00:16:58: and then the other constraint really for sure the most expensive drugs on the planet.

00:17:11: And I do not understand why, i don't work for a farmer.

00:17:16: they are hugely expensive to manufacture and there is a big issue with manufacturing avi.

00:17:24: so even in the lab when we make it in the Lab It's already an extensive reagent test on cells and animals.

00:17:36: compared other things that you might test, like small molecules or antisense oligonucleotides.

00:17:41: They're hugely expensive!

00:17:44: The key thing is consistency of manufacture and purification.

00:17:49: so when you purify it... You lose almost half of it.

00:17:53: And the field is working really hard to improve our manufacturing of AV.

00:17:58: but a key constraint Is the cost.

00:18:02: So those are kind of logistical practical issues about AV reaching the clinic through pharma.

00:18:12: I think other huge challenges about AV is safety, especially with intravenous gene therapies.

00:18:22: so we're dosing huge amounts of viral capsic and we do know that it ends up in the liver and causes liver toxicity and death.

00:18:34: a big challenge is safety and targeting with AVs.

00:18:43: Yeah, indeed so thank you very much for highlighting these major challenges.

00:18:50: I think the issue of timing to get them that treatment at their end time point related to this.

00:18:58: also the early screening.

00:19:03: Yeah, I think currently most European countries have newborn screening.

00:19:09: They already had the diagnosis by two weeks of age and they treat latest By that.

00:19:16: And then off course That has you know results in a better outcome.

00:19:21: there are studies that show that There other country mean in Cyprus we don't have yet.

00:19:27: We're waiting for it.

00:19:28: You just had England approved.

00:19:31: so I think eventually it's clear that this is the only way to go when timing so crucial.

00:19:38: I think because these are also important and of course safety, Because we want to have them.

00:19:45: you know they cause benefit ratio for favorable for our patients.

00:19:52: So do you?

00:19:52: Do you thing that any new technologies will probably help To improve safety improve the targeting Reduce, you know eventually reduce the cost.

00:20:06: How do you see all these emerging technologies?

00:20:10: So there's already lots of efforts in the field to engineer new capsids especially for systemic delivery for muscles.

00:20:20: so it's inserting peptide motifs that they can target their muscle better and de-target the liver.

00:20:31: So in that sense, I hope they will be safer and also developing new promoters so that they are more specific to your target cell type or tissue.

00:20:43: There's lots of efforts in that since now the application of AI to improve how we design these things as well... ...so there is a lot technology in the pipeline to improve AV and that we're only very much at the first generation.

00:21:04: AVs are reaching a clinic.

00:21:06: So there's a long way to go, another thing is how we understand how we dose AV.

00:21:12: so I think the clinical setting is quite different to what we see in vivo in animal models of mouse rat dog or non-human primate models I think by the time... So we often look at disease models in mice, but how well does that translate to a patient and not patients' disease state?

00:21:37: We dose currently based on body weight.

00:21:40: But Austin were trying to target my tissue.

00:21:44: so for example in Duchenne where trying to treat the muscle.

00:21:50: The Duchennes boys are often quite heavy because they run steroids muscle that you can transduce, it's fibrotic or fatty.

00:22:00: So how do we dose muscle?

00:22:02: Because it does not necessarily reflect the body weight and the doses are very high in there our safety concerns.

00:22:10: so We need to better understand How Our Models And The Dosing Reflects The Clinical Scenario.

00:22:17: There Is Huge Amount To Learn.

00:22:19: I Think Other Things Are immune response to capsids and transgenes, how can we improve the risk of immune response with different immunosuppression regimens?

00:22:34: So I think they're in the brain originally.

00:22:39: They dose directly without any immunosoppression And now we started putting them on steroids and cyrolymus or whatever.

00:22:49: so these are also evolving as well.

00:22:52: So there's lots of things to consider.

00:22:56: Yeah, I mean we always considered the CNS to be immune-privileged and probably abate systemic immunity but maybe it is not entirely so... But yeah i think that we learn a lot from immunosuppression protocols.

00:23:16: And also depends on whether patient cross immunological material negative, whether they express at all that gene.

00:23:26: Whether they have the protein in their tissues or they will react to it-to the protein In addition to the viral capsid itself.

00:23:36: so I think we're getting more sophisticated and hopefully with improved immunosuppression protocols And you know more close monitoring of patients as well, since you mentioned the Duchenne therapy being aware of some pre-existing vulnerabilities in these patients for example on the liver or heart that may make them more susceptible to complications from gene therapy.

00:24:08: So I think this we more or less covered the successes and some of the challenges.

00:24:17: So if you could summarize in a few sentences, how do you see the future of gene therapy with all the points that we discussed?

00:24:28: I think there's so many unknowns... And my vision for it is in the futures where the hematologists and oncologist worked, revolutionised their treatment of leukemias where every child's diagnosed with leukemia was then put onto almost like a clinical trial protocol that they have specific regimen.

00:24:57: So we would get say new childhood SMAs are treated in so many in this way and that we follow them for five years, then you start to better understand the outcomes at five years rather than one year which is the best treatment.

00:25:15: And I think ultimately very long term, we'll be able to read those patients with the innovations in capsules at home.

00:25:36: Great!

00:25:37: Okay yeah I think.

00:25:39: first of all thank you so much for this discussion and it was really insightful.

00:25:47: We touched upon important aspects.

00:25:51: It's clear that there has been an exciting progress in gene therapy for neurological disorders.

00:25:59: So these therapies are transformative, they change the way we think about our patients and what can do for them.

00:26:08: We clearly learn from a lot of difficulties and challenges And hopefully in future will become able to differentiate Taylor and make gym therapy more accessible safer.

00:26:28: And also we have to learn about the long term, because you know they haven't been around for very long and We have to see how?

00:26:37: You know They keep working over a long period of time as these These children that you treat.

00:26:42: They will grow up and hopefully become adults and then we have To see.

00:26:47: Hopefully they would keep doing well.

00:26:50: So thank you very much.

00:26:52: I would like to thank all who took their time to listen to the podcast And thank you very much, Joe for this really nice conversation.

00:27:15: Thank you!

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