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Wave Precision-HD Update

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A Wave of Excitement: More RNA Lowering Drugs Start Trials

As written by Julie Stauffer in 2018 Winter Horizon

As Dr. Mark Guttman described in his Symposium presentation in October, two more potential HD
treatments have reached the point of clinical trials, and his Toronto clinic is the first in the world to be testing them.

Wave Life Sciences has developed two closely related drugs – WVE-120101 and WVE-120102 – that are designed to stop cells from making the mutant huntingtin protein that is thought to be toxic to the brain.

Like the IONIS-HTTRx trial, Wave’s PRECISION-HD trials are testing drugs that “shoot the messenger” – targeting the messenger RNA (mRNA) that translates the HD gene and leads to the production of mutant huntingtin protein. By reducing the messenger, these drugs aim to stop the disease in its tracks or prevent it from developing in the first place.

However, unlike the IONIS drug, the Wave drugs target only the RNA that is associated with the abnormal CAG repeat, leaving the normal part untouched. (People with HD have both because they inherit two versions of the gene: a mutant version from one parent and an unaffected version from the other.)

That selectivity might prove to be an advantage, since the normal huntingtin protein does important things in the cell – although exactly what, we’re not quite sure, yet.

Targeting just the mutant mRNA isn’t easy, but the scientists at Wave have found a sneaky way to do
it by zeroing in on specific bits of DNA often found with the mutant gene. They call these bits SNP1 and SNP2.

WVE-120101 is designed to bind to SNP1 close to the mutant mRNA, while WVE-120102 binds to SNP2. When that happens, it prompts the cell to use an enzyme to destroy the mRNA-drug complex.

The catch is that only two-thirds of people with the HD gene also have these SNPs. And, even if someone has one of those SNPs, it may be in a place where the drug physically won’t fit. That means unlike the IONIS drug, the Wave drugs will only work for some patients.

Right now, Dr. Guttman is screening potential participants for these phase lb/lla trials. There’s a long list of criteria they need to meet to be eligible. They have to be in the early stages of HD, under the age of 65, and otherwise in good health. They have to live within a 90-minute drive of the clinic, and they have to have one or both SNPs in the right location.

On top of all that, they have to be available for a battery of tests and a series of seven lumbar punctures. “It’s very intensive,” says Dr. Guttman. “It’s certainly not for everybody.”

This is just the first study, however. If the drugs prove safe, he says, there will be more opportunities to get involved. “It’s exciting,” he says. “This is what we’ve been waiting for.”


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