First Human Gene Therapy Trial Planned For Deadly Tay-Sachs Disease

A child who died of Tay-Sachs Disease
A child who died of Tay-Sachs Disease

Imagine you have an adorable baby who's oddly slow to start sitting up. You get the child tested and to your horror, the verdict is a genetic death sentence: Tay-Sachs Disease. Exceedingly rare, but inexorably fatal. You now know that your baby likely won't live to kindergarten age, and instead of growing up will slide down into blindness, seizures, paralysis. No cure. No hope.

That is how Tay-Sachs Disease has tended to unfold, since it was first described in the late 19th century. But now, for the first time, scientists say, there is a chance — though it is far from certain — that in the foreseeable future, that merciless course could be altered.

If all goes as planned, in the second half of next year researchers from the University of Massachusetts Medical School, Massachusetts General Hospital and elsewhere will launch a clinical trial of a new gene therapy treatment in up to 12 children with Tay-Sachs Disease.

The treatment involves infusing, deep into the brain, engineered viruses that can effectively turn cells in the brain into "micro-factories" of the enzyme that is so lethally absent in people with the disease. Cats with a feline version of Tay-Sachs normally die by about age four months. The gene therapy treatment has kept them going strong beyond 18 months.

A cat with an untreated feline version of Tay-Sachs Disease
A cat with an untreated feline version of Tay-Sachs Disease

"This is the first time there's a real prospect for a possible treatment for Tay-Sachs and similar genetic diseases that affect the brain," said Susan Kahn, executive director of the National Tay-Sachs & Allied Diseases Association (NTSAD), a driving force behind the research along with other family foundations. "Parents who had affected children as far back as the 1950s are saying, 'Wow, I never thought I would see this day.'"

Now for the inevitable cautions, from UMass researcher Miguel Sena-Esteves:

“Usually, in my first breath, I tell people about the great results we’re observing in the cats,” he said. “In the second breath, I tell them there’s absolutely no guarantee that because we’re getting these results in animals, we’ll see the same in a human. We know from experiments in many, many fields that what works in another species doesn’t necessarily work in a human. If it did, we would have cured cancer by now.”

Also, gene therapy, in particular, has a past marked by some major disappointments. Touted as a potential cure for just about anything in the 1990s, it all but crashed after an 18-year-old patient died of a massive immune reaction in 1999 and it turned out that the viruses used as “vectors” to carry the genes sometimes induced leukemia.

Lately, however, gene therapy has begun to rack up successes, said Dr. Terence Flotte, dean of the UMass School of Medicine and himself a gene therapy researcher. It helped restore some vision in blind people with a rare genetic disease of the retina, he noted, and seems to show particular promise for diseases of the brain and central nervous system.


All these post-crash years, gene therapy researchers have been learning. They’re reaching, he said “a better space where no, it’s not the answer to everything but not a complete bust either. It will have certain specific niches where it will be very helpful.”

‘It gives me the shivers’

For several years, the Tay-Sachs gene therapy researchers have been laying the groundwork for the coming trial — developing the methods for delivering the therapy, testing them in mice and cats and sheep.

And they’ve been studying humans; several dozen people worldwide are diagnosed each year with forms of Tay-Sachs. Last month, the journal Pediatrics published a descriptive study of hundreds of Tay-Sachs patients or their records. It helped document the natural course of the disease, including the average age of first symptoms --at five months old — and of death, at 47 months.

It is important to have such a solid baseline to compare gene therapy patients against, said Dr. Florian Eichler, the paper’s senior author, a Massachusetts General Hospital neurologist and the principal investigator of the planned Tay-Sachs gene therapy trial.

[module align="right" width="half" type="pull-quote"]'Fast-forward 12 years, and suddenly there is hope for a child like that.'[/module]

For all the researchers’ cautions and caveats, when they described their work at a recent NTSAD fundraising event in Cambridge, there was palpable excitement among the several dozen sponsors who listened.

Blyth Lord, a children’s television producer, lost her daughter, Cameron, and her nephew, Hayden, to Tay-Sachs. When she asked the researchers a basic question about whether more than one brain infusion would be needed, her voice was full of tears.

“It gives me the shivers,” she said afterward. “My daughter has been dead for ten years, and even as I’m fully reconciled to her life and death, the fact that there is something that could help...”

“When we got the diagnosis, there was no hope,” she said. “My daughter was this beautiful child diagnosed at five months only because of her cousin, Hayden — a beautiful child like that who had no hope. Fast-forward 12 years, and suddenly there is hope for a child like that.”

A personal note: A friend of a friend invited me to moderate that panel featuring the researchers, and I was reluctant at first. Historically, Tay-Sachs has been particularly prevalent among certain populations, including Ashkenazi Jews (like yours truly) and Cajuns, and I’d heard about it since my youth because in high-risk groups, screening is used to identify carriers.

A Chicago child now living withTay-Sachs. It is now known that the "Jewish disease" actually crosses ethnic groups.
A Chicago child now living withTay-Sachs. It is now known that the "Jewish disease" actually crosses ethnic groups.

It's a great public health story: Regular screening in high-risk groups has been very successful. But the rare mutations can still be carried by anybody, and my kneejerk reaction was: Tay-Sachs? What could be more depressing? And gene therapy? Didn’t that flop?

But then I checked out the Tay-Sachs Gene Therapy Consortium and particularly the reports of dramatic results in animals. My introduction of the panel went something like: “I was all ready to express burning impatience that gene therapy is yielding so little help against such a devastating disease. But instead what I’m feeling is, “Yikes. You’re ready to forge ahead with a human clinical trial.”

What goes wrong? How to make it right?

The scientific successes that set the stage for the coming trial come replete with one of those ironic laboratory stories of an accident that led to a breakthrough — like the mouldering dishes that Alexander Fleming left in his lab over vacation, leading to the discovery of penicillin.

But first, to begin at the beginning. What goes wrong in Tay-Sachs? As Miguel Sena-Esteves explains it, Tay-Sachs and other diseases like it are essentially recycling problems. Your cells need to recycle materials all the time, a complex process involving many different proteins and enzymes.

Miguel Sena-Esteves
Miguel Sena-Esteves

When one of them is missing, as in Tay-Sachs, a lipid — or fat — begins to accumulate, much as the un-recycled plastics and papers would in your house. In the brain, that leads to a massive die-off of neurons, and relentless degeneration.

In other recycling diseases, regular injections of the missing enzyme work well, but in Tay-Sachs it is mainly the brain that is affected, and the usual injections cannot get past the blood-brain barrier.

“So the question is, how do we get around the blood-brain barrier?” Miguel said. “What gene therapy researchers figured out is that one approach would use viral vectors that encode the normal protein and you’d inject them directly into the brain.”

So, “We put in the gene that is mutated in Tay-Sachs Disease. What the virus will do is infect neurons. The vector comes in, enters the neuron, and brings in the genetic material you want. And the genetic material is going to tell the neuron, ‘Okay, you start making these proteins.’ It’s not gene correction — you can’t even talk about gene replacement. You could talk about gene supplementation — you’re supplementing the cells with a normal gene so the cells know how to make the normal protein.”

What happens in neurons after gene transfer: Recombinant adeno-associated virus (rAAV) vector carrying the normal Tay-Sachs gene instructs the neuron to make normal enzyme in large quantities. The normal enzyme is used to clear stored material in its own lysosomes, and also is released in large quantities for use by other cells.
What happens in neurons after gene transfer: Recombinant adeno-associated virus (rAAV) vector carrying the normal Tay-Sachs gene instructs the neuron to make normal enzyme in large quantities. The normal enzyme is used to clear stored material in its own lysosomes, and also is released in large quantities for use by other cells.

It was a pivotal discovery, Miguel said, that the brain’s own structure of connections could be used to distribute the key enzyme throughout the brain. It was made “by luck, admittedly, but thinking about it, it actually makes sense.”

Oops! But hey, look!

So here’s the Tay-Sachs version of Fleming’s dirty plates:

The thalamus is a central sort of a switching station in the brain that takes in all our sensory information. One day, during an experiment looking at how enzymes were distributed across brain connections, a student accidentally injected the enzymes farther into a mouse’s brain than she was supposed to, all the way into the thalamus.

“The student doing it came to me,” Miguel recalled, “and she said, ‘Clearly I screwed up the injection but look what I’m seeing.’ And suddenly we realized, ‘Oh my goodness, there is enzyme all over the brain!’”

It’s a classic lesson of science, he added, that if your results don’t exactly match what you expected, don’t just discount them. “Sometimes biology tells you things if you have your eyes open,” he said. “Biology often slaps us in the face.”

[module align="left" width="half" type="pull-quote"]“My colleagues had tried many, many different approaches in cats, and all of a sudden it was, ‘The cats are doing fine. The cats are still doing fine. The cats continue to do fine.’”[/module]

The thalamus, it turns out, can be turned into a “microfactory” for the needed enzyme that then also uses its own highway system to deliver it. So an injection into the thalamus worked in mice. Would it in cats?

Yes. In fact it worked so well that at first the researchers were sure there must be some mistake. Within one month of an injection, the normal enzymes were spread throughout the cat’s brain. They tested the cat’s genes several times, convinced there must have been some mix-up, because it was just too healthy to have the Tay-Sachs defect.

“It was becoming a bit unbelievable, actually,” Miguel recalled. “My colleagues had tried many, many different approaches in cats, and all of a sudden it was, ‘The cats are doing fine. The cats are still doing fine. The cats continue to do fine.’”

Those thriving cats helped push the Tay-Sachs Gene Therapy Consortium — which also includes other researchers from Auburn University in Alabama, University of Cambridge in England, Boston College and New York University — to accelerate its plans for a human clinical trial. At this point, it is scheduled for the second half of next year, and the money for all the pre-clinical-trial work is close at hand; fundraising is also under way for the estimated $1.5 million needed for the trial itself.

Who’s in, who’s out

Tay-Sachs Disease is so rare that there can only be limited competition for the trial’s 10 or 12 spaces. On the other hand, the desperation of parents hoping to enroll their children could be limitless.

“I can’t imagine what it’s like to have a glimmer of hope and not be able to get it,” Blyth Lord said. “Parents would do anything for their children, anything.”

Already, Miguel has received an email from a mother in Spain hoping to enroll her child in the trial. The key, he said, will be to define the criteria for inclusion in the trial very carefully, and to explain well to parents that ‘We cannot bend the criteria because if we do, we’re essentially denying all the work we’ve done.”

Choosing patients carefully could also help reduce the potential risks of the gene therapy, Miguel said, from possible immune system backlash to damage to the thalamus.

Dr. Florian Eichler of MGH
Dr. Florian Eichler of MGH

A central challenge in patient enrollment, said Dr. Florian Eichler of Mass. General, will be to identify children in the early stages of the disease. Though the first symptoms usually appear at about five months, his group's study found, the diagnosis often is not made until nearly a year later, when a great deal of damage has already been done. If the disease can be detected early, there is hope that "we can arrest it at the point where some quality of life is still preserved."

If techniques like those used in the Tay-Sachs trial are successful, Dean Flotte of UMass said, there’s a chance they could be used for much more common brain diseases, such as Alzheimer’s.

Miguel is cautious about possible uses for other diseases, but he does say he thinks gene therapy’s tipping point has arrived. In the 1990s, gene therapy had an atmosphere of “irrational exuberance, to quote the Fed chairman,” he said. “And now I think it’s perhaps a contained optimism — a circumspect optimism. People are excited, but not making all the crazy promises they used to.”

For more information on this Tay-Sachs research go to the NTSAD page here. And for an unforgettable essay about what parenting is like when your child has Tay-Sachs, read "Notes from a Dragon Mom" by Emily Rapp in the Oct. 15 New York Times.

This program aired on November 11, 2011. The audio for this program is not available.

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



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