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'First Step' Mass. Research Turns Off Key Gene In ALS That Runs In Families

In this Sept. 18, 2017, photo, Pete Frates, who was the inspiration of the Ice Bucket Challenge, is kissed by his mother Nancy while appearing with his wife Julie and daughter Lucy at Fenway Park in Boston. The challenge raised millions of dollars for research on Lou Gehrig's disease. He died in late 2019 at age 34. (AP Photo/Charles Krupa)
In this Sept. 18, 2017, photo, Pete Frates, who was the inspiration of the Ice Bucket Challenge, is kissed by his mother Nancy while appearing with his wife Julie and daughter Lucy at Fenway Park in Boston. The challenge raised millions of dollars for research on Lou Gehrig's disease. He died in late 2019 at age 34. (AP Photo/Charles Krupa)

Researchers at the University of Massachusetts Medical School and Massachusetts General Hospital report progress on a potential new weapon against the fatal nerve disease ALS: they used a virus to deliver small molecules called micro-RNAs to block a gene that causes about 2% of ALS cases.

UMass Neurology Professor Bob Brown says the method, reported in The New England Journal of Medicine, shows promise for treating the types of ALS that run in families, "because almost all of them are caused by toxic genes that misbehave. And what these treatments do is turn off those misbehaving genes."

But Brown says it will be years before this sort of gene-silencing could be used broadly in ALS patients. The disease typically kills patients within five years, and despite extensive research, funded in part by the high-profile "ice bucket challenge," it remains incurable.

The following are edited excerpts of an interview with Dr. Brown, who is also director of the UMass Medical School's Program on Neurotherapeutics:

How would you sum up what you found?

We have used a virus to deliver into the spinal fluid a small DNA molecule that can turn off an ALS gene. The clinical result is that we see a reduction in the spinal cord of the activity of the gene that we have targeted. We think there were some suggestions of clinical benefit, in terms of the strength of the patient, but that still remains to be reaffirmed in a much larger study.

How is this a first?

To my knowledge, this is the first time that a virus has been used with this DNA molecule, called a micro-RNA, to turn off a gene that causes a degenerative disease in the brain. It's the first time that a virus and a micro-RNA have ever been used to turn off a disease gene — not just with ALS, with any disease. It's a tentative, small toe in the water. It's a first step.

Is it a dawn of a new era, of a new tool against diseases?

We're all on the cusp of a new era of using biologic reagents — antibodies, proteins, and things like DNA and RNA — as treatments. This is all new. But it's also specifically a dawn of a new era in the sense that we're using the virus and this particular reagent for this disease. We hope that this will be a path forward for most of the adult-onset brain degenerative diseases.

I think this holds very substantial hope for treating at least the familial forms of the illness, because almost all of them are caused by toxic genes that misbehave. And what these treatments do is turn off those misbehaving genes.

These are pilot studies that look very promising, using two different strategies. They will have to be reassessed and confirmed in much larger studies over the next two or three or four years.

It was back in 1993 that you discovered the ALS gene at issue here, called SOD1. How would you comment on how long it's taken to get this far?

We never thought it would take this long. In 1994, we published a paper with colleagues at Johns Hopkins showing we could turn off the gene in a petri dish. But moving from the petri dish to the human setting required all these additional years. For our study, which uses a virus to deliver the silencing tool, the key advances were in virology: finding the right virus that can safely be administered to a human.

In fact, the dean at our medical school was the first person ever to use this particular virus in a human. So for me, it was a very natural marriage to take the SOD problem to him. It's also the case that the people who discovered how to turn off genes are also at UMass. So it was quite logical to go to them and say, 'Guys, help out with this problem.'

And you're saying this opens an avenue for all adult-onset neurodegenerative diseases, including Alzheimer's and Parkinson's?

I think it opens an avenue for a large family of those diseases, because many of them, certainly the familial forms of them, almost always act through genes that misbehave, that make miscreant proteins or RNA that is toxic, and what these therapies do is suppress that activity. So I think there's a broad set of applications and the field knows that. Big Pharma is working on this, and many academic labs. My problem is that I'm chronically optimistic and I'm certainly optimistic here, to tell the truth.

So could this be called the launch of gene therapy against neurodegenerative diseases?

I think one has to split a hair here. Usually, when we think about gene therapy, the term often conveys putting back a missing gene. And here what we're doing is suppressing a misbehaving gene. You might call it gene suppression therapy. It certainly is the onset of gene suppression therapy.

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Carey Goldberg Twitter Editor, CommonHealth
Carey Goldberg is the editor of WBUR's CommonHealth section.

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