Rare Neurological Diseases: Spinal Muscular Atrophy and Huntington's Disease - Episode 5
Peter L. Salgo, MD: We’ve been teasing this. So why don’t we start paying this off a little bit.
There are potential treatment options. It’s the first time in my career I’ve ever heard them with regard to Huntington disease. There’s an antisense oligonucleotide. I even got that out in 1 breath. What are we talking about?
John Brandsema, MD: We’re starting to become more and more fluent in some of these new techniques.
They’re genetically targeted therapies, so they may not necessarily be altering genes themselves but rather the expression of those genes. I think this is a great example of it. In Huntington disease, what we have is a toxic gain-of-function. Because of this trinucleotide repeat, there’s too much of this Huntingtin protein accumulating in cells, and this is what leads to...
Peter L. Salgo, MD: But, that’s the disease.
John Brandsema, MD: Yes.
Peter L. Salgo, MD: A toxic gain-of-function.
John Brandsema, MD: Right.
Peter L. Salgo, MD: You’ve got too much of a gene.
John Brandsema, MD: These antisense oligonucleotides that have been developed are looking at reducing the amount of that Huntingtin protein to try to ameliorate the progression of the disease. What we have right now are phase 1 and phase 2 data from 1 program from a company called Ionis Pharmaceuticals, Inc, that is looking at reducing the Huntingtin protein. The early data from that are quite encouraging. Based on preclinical models, they have a correlate of reducing Huntingtin protein in the CSF [cerebrospinal fluid]. What that means is this is in your cortex and particularly in the basal ganglia, which is the most affected region in Huntington disease. In the patients who have been dosed in this study, there is a reduction in the Huntingtin protein in the CSF, which you can then use these algorithms to try to predict how much their Huntingtin protein is reducing in those critical areas of brain function.
Peter L. Salgo, MD: Does the decrease in Huntingtin protein correlate to a decrease in symptoms?
John Brandsema, MD: It’s exploratory in terms of the efficacy data. This isn’t placebo-controlled data. But, it looks that some of the functional skills that measure some of the symptoms of Huntington disease are improving at the 3-month point after treatment in this study. However, there are many aspects of it that are still being actively researched. The optimal dose hasn’t been established. This was dose finding, and there were multiple dose levels within the study. It seems as if early safety data are quite encouraging that this is well tolerated. But, this is also something that has to be looked at very carefully when you’re using a new approach like that.
Peter L. Salgo, MD: It’s phase 1 and phase 2, right? Let’s not go crazy here. But this is the first time I’ve heard anything other than supportive care and some therapy and care going forward when you become less able to care for yourself. This stuff at least holds the promise, the implication, of turning the disease down and maybe off, which raises a question to me, simply. If you’ve been overproducing, whatever these proteins are that the gene is coding for, why did it take so long to show up? Why does it show up in your 30s and 40s and with the caveat sometimes it comes earlier? Why is it taking until that age for this genetic abnormality to cause symptoms?
John Brandsema, MD: I think that’s something that we really need to understand better in terms of what the other genetic modifiers are and what might be things that might be best predictors of when people will become symptomatic. The literature around the silence of neurodegenerative disease before it becomes clinically apparent is quite discouraging. My best example I can think of as a neuromuscular specialist is ALS [amyotrophic lateral sclerosis]. There’s a lot of work that’s been done in people who have genetic forms of ALS where they try to use clinical markers, even things like electrophysiology, to follow patients who are known to be predisposed to these disorders.
You don’t pick anything up, but in the preclinical model, you can actually see degeneration of what’s going on in the disease well before there’s anything that we can actually see in the clinic. Then the question becomes, in something like this—which is an intrathecally delivered medication, so it requires lumbar puncture sequentially—when is the right time to put a patient on that kind of intervention in terms of having the best possible outcome of the disease without having a burden of having to be treated when they don’t need it? This is a really difficult thing to pinpoint.
Peter L. Salgo, MD: This is for intermittent LPs [lumbar punctures] with doses of the drug as it’s currently configured. I was wondering if there would be a reservoir in a pump if that’s what might be the end result of all this?
John Brandsema, MD: Sometimes that’s the best delivery method, but it depends on the particular treatment that’s being devised.
Peter L. Salgo, MD: Where are we in the pipeline with this? What’s going on?
John Brandsema, MD: The data available currently are from phase 1 and 2 studies through a company called Ionis Pharmaceuticals, Inc, but this has now moved into phase 3 studies with Roche-Genentech.