The Gene Therapy Dilemma in Huntington Disease


With the planned submission of an IND for the first AAV gene therapy for the rare genetic condition, some experts are wondering if things are moving too quickly.

Dr Neepa J Patel

Neepa J. Patel, MD, a movement disorder specialist in the Henry Ford Health System

Neepa J. Patel, MD

Currently, there are no existing therapies that can alter the course of Huntington disease. But as the research and popularity of gene therapies continue to grow, the interest in them for the genetic disorder has as well.

In April 2018, uniQure, a gene therapy company based in Amsterdam, The Netherlands, announced promising data for AMT-130, am AAV5 vector gene therapy intended to inhibit the production of mHTT, the mutant Huntington gene. The company plans to submit an Investigational New Drug application to the FDA later this year, which would mark the first AAV gene therapy to enter clinical development for Huntington.

Like many others, for Neepa J. Patel, MD, a movement disorder specialist in the Henry Ford Health System, the prospect of the introduction of gene-altering therapies into the Huntington space is exciting. Although, she noted that it carries an important caveat. To discuss this, as well as the currently available treatments, Patel spoke with NeurologyLive in an interview.

NeurologyLive: In the Huntington space, is there anything currently available that’s helping?

Neepa J. Patel, MD: There are some pretty good therapies to treat the most prominent portion of Huntington disease, which is the movement disorders, and there have been a few new drugs that have come to market in the last few years that I think address that pretty nicely. Huntington is more than just a movement disorder. It’s got pretty profound dementia and a psychiatric behavioral component to it, which is really challenging to treat. We kind of bleed over to our psychiatry colleagues in the management of the bipolar disorder and those meds to get the handle on it, but we don’t have a great handle on that and a great targeted therapy for Huntington itself.

The bigger thing is that this is a classic Mendelian genetic disorder and we’ve known for so many years what the abnormal gene expression is, but we haven’t really been able to modulate it or modify it apart from family planning and gene selection and things like that when conceiving. The things that are coming up in the pipeline that are the most exciting being that now they are looking at gene silencing therapies to close the expression of this abnormal protein product. That would be fantastic.

People talk a lot about the CRISPR technology that’s there and writing out the Huntington gene and swapping it out for the normal one. There’s a lot of ethical and safety and various other things that need to be sorted out before we start using that. But, I think at least in the realm of gene silencing and suppressing the expression of the abnormal gene, that hopefully will be effective. That’s in its very preliminary stages of evaluation as well.

Is there an ethical dilemma surrounding gene therapy among your colleagues?

If we could just isolate it to rare genetic disorders, it would be a slam dunk no-brainer, but this technology is available for everything. But, 1., you’re not going to be perfect in your rewriting of this Huntington gene, and 2., this gene is foundational to the nervous system. If you manipulate it, you run the risk of having devastating consequences that we can’t even imagine. I think that is one of the big things holding up, at least in Huntington, but also in other genetic disorders, is that these genes create protein products that are so important to the structure and function of the human body. If we were to change it and mix up one of the coding regions and change this protein, what would happen and what other downstream effects would come from this? I think that is one of the big things.

The other ethical dilemma that comes with it is if we can identify somebody with Huntington and write out their genetic code—let’s say they also have an at-risk Alzheimer’s gene because that is less definitive for Alzheimer’s. Then you say, “Oh, now that you won’t have Huntington, let’s also write out your Alzheimer’s. Then we found these couple of genes that make you more intelligent, let’s write that out, too.” Then you’re going to start having a menu and tailor-made human beings. It can go into all of these dystopian directions—which is the huge ethical dilemma that I think the community at large in the genetics and research fields are really thinking about it and trying to address proactively.

Has there been enough proactive thought about it?

I think it depends. In this world, you can always talk to like-minded people and never really hear the opposing viewpoints in any meaningful way. I will say, at the big conferences I’ve been to, at the Movement Disorders Society, when they start talking about gene silencing and gene editing and what’s on the horizon, all the speakers talk about this. They don’t spend more than 2 to 3 minutes in their hour presentations on it, but they do touch on it. There truthfully, isn’t a large committee, nationally or even internationally, to make a position on this. It’s really the people developing the technology that say, “Hey look at what we’re doing, this is pretty awesome.” They want it out there and they want it available for everybody, and a lot of people think this could be great for x, y, and z reasons, but there are a few people that think about it on a larger scale but not in a meaningful way. At least from what I hear about, if it gets to this point where it is safe, it will probably come to the market without any kind of true restrictions to it, and somebody will figure out how to use it to their own purposes. But I don’t think it’s slowing down the research by any means.

Transcript edited for clarity.


uniQure delivers


presentation on


set of preclinical data on AMT-130 in Huntington's disease at the 2018 American Academy of Neurology Annual Meeting [press release]. Amsterdam, The Netherlands: uniQure; Published April 25, 2018. Accessed September 24, 2018.

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