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Early Report: Baby Treated With Gene Therapy For Deadly Tay-Sachs Disease Appears To Stabilize

Patient Cenzy Thornton (who is not the baby treated with gene therapy) and her father at the 2017 Annual Family Conference of the National Tay-Sachs and Allied Disease Association. (Courtesy NTSAD)

It's a very early report, from just two patients, only a few months after treatment. But UMass Medical School Dean Terence Flotte this week shared at a conference what could be landmark news about a terrible genetic disease: Two young patients with Tay-Sachs disease showed no ill effects from a new gene therapy that aims to correct the defect at the heart of the disease.

One of them, treated at just 7 months, has appeared to stabilize instead of following the typical quick slide toward death by age 4.

"It seems right now that she's not degenerating," Flotte said. "But I would say it's too early to say that definitively."

Tay-Sachs is a fatal disorder that tends to affect babies of Eastern-European Jewish ancestry, along with other ethnicities including Cajun and Irish. They usually seem to develop normally for the first few months, but as the disease kills off their nerve cells, they lose the ability to move or breathe on their own.

Flotte says the brain MRI of the baby treated at 7 months looks encouraging, and a clinical trial in more than a dozen patients is expected to begin soon.

Edited highlights of our conversation follow.

You've just presented at a gene therapy conference. What did you report?

We reported the first two patients ever treated with gene therapy for Tay-Sachs disease — two infants treated at UMass Memorial Medical Center. What we presented was that these two patients were both treated safely. The vector [the engineered virus that delivered the genetic fix] was administered directly into the brain.

We saw bio-activity, which basically means that we partially restored the enzyme that is missing in Tay-Sachs disease. And the patients were able to tolerate that safely. Also, in one of the cases, with the patient treated early in the course of the disease, we've seen some stabilization of the patient's condition.

What do you mean by stabilization?

One of the patients was treated at 2-1/2 years of age, and that patient had really advanced disease. And we've seen the biochemical effect, but really no clinical effect.

The second patient was treated between 6 and 7 months of age, and in that patient, it appears, although it's still very early, that the patient may be having some continued preservation of her ability to sit up and control her muscles. She's basically seeming to have a more gradual progression — at the current time, really being stable — at a time point when we might be expecting her to lose some of these developmental milestones.

The best way to explain it is that if a normal infant begins to sit up at around six months of age, Tay-Sachs babies do that, but then they tend to lose the ability to sit up some time between 10 months of age and maybe 15 months of age. The last time we assessed the patient, at 10 months of age (and she's now close to 12 months of age), she seems to not be losing any of the strength required to sit up. We have her older siblings for comparison, and it's encouraging that she seems to be progressing less than they did. We also saw some encouraging signs on her brain MRI.

It seems right now that she's not degenerating. But I would say it's too early to say that definitively. If you think about the progression of development as the slope of a line, the line is flat at this point. It's not going up or going down. The next assessment will be very important, to see whether she's continuing to be flat, which would be a major benefit, or whether she's regressing but just a little bit more slowly.

When you say flat, she's also not advancing as a typical child would? 

That is right. It looks like preservation of function rather than gaining. But her oldest sibling died before his third birthday. So considering how fast these patients can decline, a preservation or stabilization could be very important.

It's important to note, too, that we are just at the very beginning. The first patient got the vector injected just into the fluid around the brain, the cerebro-spinal fluid, not into the brain tissue.  The second patient got a portion of it injected into the thalamus, which projects out to the entire brain tissue. It's kind of the relay center of the brain, and it can actually ship enzyme out all over the brain.

No one's ever tried that in a humans before, so that was really an important milestone, that intra-thalamic injection. As the trials progress, a larger dose will be injected into the thalamus.

Why has there never been an injection into the thalamus in humans before? What's the challenge?

One challenge is that it is a completely  irreplaceable structure. Effectively, all motor and sensory function relays through the thalamus. So if you were to have bleeding or injury to the thalamus, it could cause a stroke or a persistent pain syndrome. So it is somewhat risky. On the other hand, when you're dealing with the infantile form of Tay-Sachs, it's so tragic that it warrants a rather risky approach.

It's been done many times in animals, but this was the first time doing it in patients.

What's next? A full clinical trial? 

Yes, Axovant has licensed the program. This first program was done all at UMass Medical School and UMass Memorial Medical Center, and the program is now licensed to Axovant, and they are planning in the near future to do a Phase 2 trial, which we will still be involved in.

It will entail increasing the proportion of the vector injected into the thalamus, so that we will get to the exact proportional dose that was used to correct all of the different animal models that have been treated: a mouse, a sheep and a cat model.

UMassMed Magazine has more on the school's Tay-Sachs gene therapy work here.

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