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2023-03-30T01:55:17.3264249Z
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Segment:1 Genetic therapies for neurodegenerative diseases with Sarah Tabrizi.
SARAH TABRIZI: So my name's Professor Sarah Tabrizi. I'm a professor of neurology at UCL Queen Square Institute of Neurology in London I'm also the director of the UCL Huntington's Disease Research Centre and co-head of Neurodegeneration at UCL. So my research and everything I've done and all my work for the last 23 years since my PhD is all focused on one disease, on Huntington's disease. And I have done a lot of work on cellular mechanisms of neurodegeneration using prion cell models for cell biology models.
SARAH TABRIZI: But I run a bench to bedside clinic research team that does research, wet lab basic science research, right through to first-in-man studies and now focus on one disease, Huntington's disease, which is a genetic dementia which all of my work is focusing on trying to find an effective therapy.
Segment:2 How far has the development of genetic therapies come?.
SARAH TABRIZI: So in Huntington's disease, it's a really big subject. Huntington's disease is a purely genetic dementia. So the only way you get Huntington's disease if you inherit the mutant gene from an affected parent.
SARAH TABRIZI: And because it's a genetic dementia, a lot of work has been focused on trying to develop therapies that target the DNA or the RNA to reduce production of the toxic protein. And so I led the world's first Huntington lowering study, which was an antisense oligonucleotide study. But also there are other therapies targeting DNA and RNA through gene therapy, through other ASO approaches either in the clinic or in preclinical development. So I would say, in Huntington's disease, it's a huge area.
Segment:3 What are the challenges surrounding clinical trial design for genetic therapies in neurodegeneration?.
SARAH TABRIZI: Well, I think that's the big issue in neurodegeneration that we don't have effective therapies. And there are many challenges. The brain is a very difficult organ to treat. It's not like the bone marrow or blood where you can take out the bone marrow. You can treat it with something like CRISPR, and then put it back.
SARAH TABRIZI: You can't take the brain out, treat it, and put it back. So the brain is in a very privileged area, because it's surrounded by the blood brain barrier, which protects it. And it's also a large organ. So the big challenges are delivering genetic therapies, distribution of genetic therapies to cover enough of the brain.
SARAH TABRIZI: We can actually pretty well cure a Huntington's disease mouse. But a mouse brain is the size of your fingernail. And the human brain is many times larger. And so the challenges are, can we get the best agents for delivery and distribution to enough of the brain to make a difference.
SARAH TABRIZI: I think the other area that's a big challenge is when to treat. And I think a lot of focus is on treating very early in the disease. And I have a huge interest in that I think we need to go earlier.
SARAH TABRIZI: I think eventually we need to develop therapies for pre-symptomatic Huntington's disease gene carriers who are clinically well to try and prevent the disease occurring. And I think these are big areas of challenge and discussion in clinical trials.
Segment:4 How can we overcome these challenges?.
SARAH TABRIZI: Many different approaches-- I think preclinical work in large animals is critical. You have to do large animal preclinical work before you go into a human. And that's really because you have to be sure, before you go into a first-in-man study, that you get into the brain regions you need to treat.
SARAH TABRIZI: Better delivery methods are needed and better viral vectors for gene therapy that are able to transduce the whole human brain, not small regions. Because treating a small region in a whole brain disease, like Huntington's disease or any of the other neurodegenerative diseases, may not make enough of a difference.
SARAH TABRIZI: And I think, also, on the other side about when to treat we need to understand much more about pre-manifest phase of disease, much more about biomarkers that could be used in trials, and also to get the regulatory authorities, FDA and European Medicine's Agency, to come on our side to allow us to treat as early as possible in these diseases.
Segment:5 What technological advancements could help bring these therapies to the clinic?.
SARAH TABRIZI: I think a number. One, if we could get better biomarkers for pre-manifest HD, that we could do trials over short periods.
SARAH TABRIZI: I think better delivery methods, AAV virus, for example, that could transduce the whole human brain would be a game changer. And also, even with agents like antisense which you have to be given repeatedly through intrathecal lumbar puncture injections-- a way of encapsulating them so they last longer or whether they could be delivered via pumps, which didn't need to have repeated lumbar punctures.
SARAH TABRIZI: So I think all these are important technological advances that need thought and work.
Segment:6 What are the next steps for RG6042?.
SARAH TABRIZI: So this was the trial that I led and was the global PI for. And we recently published the results in the New England Journal of Medicine. So this was the first study in any neurodegenerative disease to show suppression of a mutant protein in the CNS of patients with an adult neurodegenerative disease.
SARAH TABRIZI: So it is a world's first. And what we did, we started in 2015. We dosed 46 patients with increasing doses over five cohorts with 3 to 1 active to placebo. The primary outcome of the study was safety and tolerability. And it was found to be safe and well-tolerated. The secondary outcome was the pharmacokinetics and could we measure the ASO in plasma and CSF.
SARAH TABRIZI: And a key exploratory outcome was, could we see evidence of target engagement with mutant Huntington? And that would tell us that the antisense got to the brain with our intrathecal lumbar puncture delivery method that we helped develop, and then show that we got target engagement. And we did get significant lowering of the mutant protein showing for the first time that an antisense in adults through a lumbar puncture injection could get to the brain, could engage with its target, and lower the level of a toxic protein by binding to the messenger RNA.
SARAH TABRIZI: So it was a huge step forward. And I think it's been of huge importance in neurodegeneration. It's now led the way for trials in Alzheimer's disease, in Parkinson's disease, and ALS based on the results from the Huntington's trial.
SARAH TABRIZI: The next steps are the patients are all in an open label extension where they're all getting the active drug, which will tell us about long-term safety and the effects of sustained Huntington lowering.
SARAH TABRIZI: And also, Roche opted in, bought the program, and they're taking the program forward into a large worldwide phase III study of 660 subjects with two doses versus placebo. And this is a critical Phase III to see if giving the antisense regularly actually slows disease progression in patients with symptomatic disease.
Segment:7 Where do you see the field progressing in the next 10 years?.
SARAH TABRIZI: I think this is very exciting.
SARAH TABRIZI: I think the next 10 years will tell us the readout from the Phase III antisense trial. There will be gene therapy trials coming in that we can see how they do. I think this is really important. It's injections into brain regions to see if you can stop the disease causing protein. So I think the next 10 years is going to tell us a lot about really if genetic therapies pan out and turn out to be an effective disease modifying therapy.
SARAH TABRIZI:
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