Latest / VJNeurology Podcast / ALS Gene Therapy Insights with Prof. Dame Pamela Shaw

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ALS Gene Therapy Insights with Prof. Dame Pamela Shaw · VJNeurology Podcast

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  Hello and welcome to today's podcast from the Video Journal of Neurology.
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  We're an open access video journal sharing the latest news in neurology across all major disciplines.
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  Our regular podcast will bring you exclusive insights from renowned experts
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  on hot topics in their fields.
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  In this episode, Professor Dame Pamela Shaw from the University of Sheffield
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  will be discussing the research surrounding gene therapy for ALS and explaining
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  why gene gene therapy is a good approach.
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  Professor Dame Pamela Shaw will start off by outlining the progress in genetic therapies for ALS.
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  She explains the genetic component of ALS and discusses five distinct therapeutic
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  targets currently under clinical investigation.
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  There is a big genetic component to ALS.
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  So, you know, roughly somewhere between 5 and 10% of patients will report a family history.
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  Someone else in their family has had the condition.
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  But even without a family history, if you check for all the known genes,
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  and there are more than 30 of them now,
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  quite a proportion, at least 20%, will have a gene that predisposes them to developing MND.
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  I think that there is a childhood form of motor neuron disease called spinal
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  muscular atrophy or SMA.
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  And that really, you know, blazed a trail for showing that motor neuron degenerative
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  disorders are treatable if you get the right treatment.
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  So in SMA, there is a deficiency of protein called the survival motor neuron protein,
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  and genetic gene therapy was used to show that if you boost the level of that SMN protein,
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  you make a remarkable difference to the course of that disease.
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  In its most severe form, it causes babies to die within the first two years of life.
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  And with a single gene therapy injection, you know, there were toddlers of three or four running around.
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  I have a lovely video of a little girl with type 1 SMA dancing with her neurologist
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  when she went to a clinic visit. it.
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  So I think that really was an exciting
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  phase in the development of genetic therapies for MND like disorders.
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  And we did a lot of, in my research institute in Citroën, we did a lot of the
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  preclinical work in mouse models and so on, showing that that approach could work.
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  So now it has been applied to adult ALS or motor neuron disease.
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  And the first breakthrough really was related to the SOD1, SOD1 gene,
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  which was the first gene found to cause familial ALS back in 1993.
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  But what we need to do with SOD1 is lower the expression of the SOD1 protein
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  because the gene change causes a toxic gain of function.
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  So we needed to lower, whereas in SMA, we're raising the level of a protein.
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  For SOD1 MND, we need to lower the level of the SOD1 protein.
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  And again, our laboratories in Sheffield and other labs around the world showed
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  in cellular models and mouse models that lowering the level of the SOD1 protein was beneficial.
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  And also you could measure that the treatment was doing the right thing by measuring
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  the level of the SOD1 protein.
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  You could see it being lowered in the cerebrospinal fluid.
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  So that all gave confidence that that approach might work in human beings and
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  so we used a treatment called Tofacin and first in human phase one trials,
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  then phase two and phase three.
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  And Tofacin, it's not a gene therapy carried by a viral vector into the nervous system.
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  It's what's called an ASO, an antisense oligonucleotide that only lasts for
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  about a month and it has to be given via a lumbar puncture into the cerebrospinal fluid.
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  So, we did those trials and really very exciting results.
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  Within three months, we could see a lowering of the SOD1 protein in the spinal fluid.
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  And I've done, I think, about 25 clinical trials for MND patients.
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  And this is the first one where patients, after a few months of therapy,
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  not immediately, were reporting improvements.
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  My muscles are getting stronger. I can do things today which I couldn't do six months ago.
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  Climbing up the garden steps, writing my Christmas cards.
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  I couldn't do it at all last Christmas because my right hand was so weak.
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  This year, I've written all my Christmas cards. So really exciting.
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  And obviously, that Tofferson treatment following the phase three trial has
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  been licensed to become available for patients in the US.
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  And also the EMA, the European Medicines Agency, have also recently approved it.
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  We're waiting still for NICE to approve it in the UK. But in the meantime,
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  it's available to patients.
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  So Biogen have an expanded access program.
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  So it's available to patients.
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  So that was the trailblazer. And the other really exciting thing that came out
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  of the Tofferson trials is that there is a biomarker or a protein that you can
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  measure that shows the treatment is working.
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  So motor neurons are stuffed full that their internal skeleton, if you like,
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  is formed by neurofilament proteins and they have a big long axon or process
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  coming out of the spinal cord or brainstem that might be a meter long.
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  So they've got a lot of neurofilament proteins within them.
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  And as the motor neurons get damaged and die, neurofilaments are released into
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  the spinal fluid and then the blood.
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  And we could show with tofacin that the level of those neurofilaments came down.
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  It decreased quite dramatically by at least 60%. So that really shows that you're
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  slowing down or preventing the damage to motor neurons.
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  So not only was it a treatment that seemed to keep a lot of patients stable
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  or even improving for a while,
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  But we have a biomarker in terms of measuring neurofilaments that's going to
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  be very useful for future clinical trials.
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  So that was the first one. There are now several antisense oligonucleotide trials happening.
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  So there's one for a rare genetic variant of MND caused by a change in the FUS gene.
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  And there was a very dramatic example of a young teenager from Germany who had the FUS mutation.
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  She was absolutely paralyzed, couldn't move her arms or legs,
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  and she started to have this genetic therapy with an ASO to lower the level of Fuzz.
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  And in December, she walked onto the stage with her mum at the end of the International MND Symposium.
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  So Fuzz, it's quite a rare genetic variant, but the results are looking quite
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  positive. We did try two genetic therapy trials for the commonest genetic variant that can cause MND.
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  That gene has got an awkward long name, C9ORF72, but it accounts for about 10% of MND overall.
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  And we've tried two ASO trials for that commoner genetic variant and it didn't
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  work. so it didn't work like it did for SOD1, so we're back to the drawing board for C9 ALS.
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  And there are other trials going on that involve genetic therapies,
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  but are applicable to MND patients more broadly,
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  so patients without a defined genetic mutation. So one of them,
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  is again an antisense oligonucleotide or ASO to lower the level of a protein called Ataxin-2.
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  Lowering Ataxin-2 seems to get rid of the protein clumps, protein aggregates
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  that form in motor neurons as they're getting damaged, and they're made up of a protein called TDP43.
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  So most MND D is a TDP-43 proteinopathy.
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  And there's evidence from preclinical work that lowering the level of Ataxin-2
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  helps to get rid of those TDP-43 protein clumps.
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  So that trial is ongoing. And there's another trial aiming to...
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  So in the presence of this TDP-43 proteinopathy, the protein called Stathmin-2
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  gets misregulated and Stathmin-2 is very important for the health of motor neurons.
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  It gets lowered in the presence of these TDP-43 clumps and there's a genetic
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  therapy trial aiming to increase the level of that important Stathmin-2 protein.
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  So there's a lot going on and there are more genetic therapies in the preclinical
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  space as well that may come through in the future.
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  So I think, you know, for such a cruel disease, genetic therapies are a very
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  exciting new development, a real game changer, I would say.
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  Next, we will hear more from Professor Dame Pamela Shaw about the pathophysiology
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  of C9-ORF72-mediated ALS and why there have been recent clinical failures in
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  the development of antisense oligonucleotides to treat C9-ORF72-mediated ALS.
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  ASOs directly act on the source of the pathogenesis and can change RNA and modify
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  protein expression. C9-ORF72 is the most common genetic cause of ALS,
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  therefore targeting this protein should help to resolve ALS.
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  However, this has not been seen in clinical trials and is likely due to the
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  ASO only targeting the sense strand.
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  This is a sensible idea as there is evidence pointing to a toxic role of the antisense strand.
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  The C9-ORF72 gene is a more complicated gene.
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  And genes are made up of exons, which are the bits that code for the proteins to be produced,
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  and then introns, which are the linking bits of the DNA that connect the coding exons.
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  And in C9, there is a sequence of bases.
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  Four Gs, two Cs, that normally you have up to 30 of those in that intron.
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  But in C9 ALS, there can be hundreds or even several thousand of those repeats.
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  So it's a hexanucleotide expansion in a linker sequence, an intron of the gene.
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  And it took a long time to find that.
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  And what happens is that that expansion gets made into a messenger RNA.
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  And normally, or a pre-messenger RNA,
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  normally that linker sequence should be cut out in the nucleus and then just
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  the coding parts of the C9 gene get out of the nucleus into the cytoplasm of
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  the cell where the proteins are made.
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  But that linker sequence is sticky,
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  so it sticks to certain RNA binding proteins and sticking to those proteins
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  instead of it being disposed of in the nucleus,
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  that stickiness and sticking to particular nuclear export factors mean that
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  that abnormal sequence that should be disposed of in the nucleus is getting out into the cytoplasm.
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  And getting to the ribosomes, which are the factories where proteins are made,
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  and that abnormal sequence forms these toxic dipeptide repeat proteins that
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  are toxic to motor neurons.
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  And the...
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  Two antisense oligonucleotide trials that were supported by Biogen and then
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  another company called Wave Therapeutics,
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  that expanded region can be read in two directions.
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  So it can be read in a sense direction going one way and an antisense direction going the other way.
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  And because of that bidirectional reading, there are five different toxic dipeptide
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  repeat proteins that can be produced.
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  And the airso in both trials only tackled the sense strand and leaving the antisense
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  untackled with, if you like.
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  And so we think that that may be a major reason why the trials weren't effective.
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  We don't know the full reasons and the publication relating to the Biogen trial,
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  I hope, will appear in an important journal very soon.
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  We've just done the third revision of it, so it should be out soon.
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  But that's the major thinking that it probably didn't work because the antisense strand wasn't tackled.
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  And there's some evidence that the proteins produced from the antisense reed
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  are more toxic to motor neurons.
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  So it's kind of back to the drawing board to try a new approach for that condition.
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  Very important because the C9 gene change causes not only ALS,
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  but it can also cause frontotemporal dementia.
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  So we haven't given up on that, but we haven't got the right therapy for it yet.
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  It's a more complicated gene in some ways than SOD1 is.
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  We will hear Professor Dame Pamela Shaw's thoughts on the Taforsan clinical trials.
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  Taforsan is a drug designed to treat SOD1-mediated ALS.
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  While detectable changes in biomarkers were observed in the early trials,
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  enhancement in motor function was only observed one year on from the start of the trial.
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  You know, when you do a new trial, it always gives hope to the patients.
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  And sometimes they think, oh, you know, I'm doing quite well on this.
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  But never has anyone reported, actually, you know, I'm stronger than I was a few months ago.
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  So very exciting. But we have to be patient.
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  So in the Tofacin trials, the biochemical things you could measure in the blood
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  or cerebrospinal fluid, we could detect quite early, between 8 and 12 weeks,
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  but the clinical benefits took longer.
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  And that's not surprising because Because, you know, damaged motor neurons have
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  to re-sprout and reconnect with muscles.
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  And, you know, that can take a while to achieve.
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  So I think we've learned a lot from the Tofferson trials, including we need
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  to be patient to see clinical benefit.
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  Presently, Tofferson is approved by the FDA, although it is waiting for NICE's
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  decision to bring the treatment to the UK.
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  Her concerns about the cost of Tefosin, although other diseases have a range
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  of approved yet expensive therapies, Professor Dame Pamela Shaw will share her
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  perspectives on the cost effectiveness of gene therapies for ALS.
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  That is a real healthcare issue we're going to have to tackle,
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  I think, because the genetic therapy, this time using a viral vector for spinal muscular atrophy,
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  I believe that can be given as a one-off therapy because the viral vector carrying
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  the genetic message means that it can last a long time,
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  but it was kind of more than a million dollars per person, I think.
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  And it has been used within the NHS, but in quite a small number of patients.
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  Fortunately for SMA, other treatments have also come forward beyond Zolgensma,
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  which is the viral vector genetic therapy.
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  So we have Spinraza and Nucinersin now that are also effective.
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  So it's a challenge. These are expensive therapies to develop,
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  expensive clinical trials to do.
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  And I guess the pharmaceutical companies feel they have to cover their costs.
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  We haven't tackled yet what Tofacin might cost in the UK.
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  But I think we've got to keep going. You know, multiple sclerosis is a good example.
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  There are now probably 12 or 13 disease-modifying therapies for MS.
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  They were all very expensive at the start, but, you know, they've got approved.
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  And sometimes you can get them approved through the NHS in the UK if you're
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  continuing to collect data from the patients and build up confidence that this
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  really is an effective therapy.
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  So we're waiting for NICE to...
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  Give their opinion about this at the moment. They're directing it down the wrong
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  pathway for consideration.
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  It should be a highly specialized treatment approach because SOD1 patients are only 2% of MND cases.
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  So there will be 100 patients or less in the UK with that particular variant.
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  But I think some of our MND clinical study group group members are going to meet with NICE,
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  I think either later next, this week or early next week to discuss that in more
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  detail. But it is a challenge.
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  How do you, you know, I think it's a challenge with a lot of new therapies,
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  really cost effectiveness and how can we afford it within our NHS system?
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  So I think we have to just take each one on a case by case basis and try and
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  persuade the powers that be that it is worth doing.
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  And, you know, I think we really have to push for MND. I think it's the most
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  cruel disease in medicine.
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  And, you know, we've got had so many expensive cancer therapies be approved.
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  I think we need to push very hard for this one to come through.
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  Those were all the updates we had for you today. Thank you so much for tuning
• 20:23
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