Clinical trial results expected for neurodegenerative DNA drugs
The results of clinical trials of designer DNA drugs that treat neurodegenerative diseases are expected to be released next year. California-based Ionis Pharmaceuticals is testing antisense oligonucleotides that mute the mutant genes behind conditions such as Huntington's and Lou Gehrig's diseases. If early-phase results show a reduction in the levels of proteins thought to trigger malfunctions in patients' nervous systems, larger trials are likely to follow.

What started more than a decade ago as a hunch among a small group of San Diego researchers has grown into real hope for treating currently-incurable neurodegenerative diseases.

Next year, Carlsbad’s Ionis Pharmaceuticals is expected to release clinical trial results for Huntington’s and Lou Gehrig’s diseases that use designer DNA drugs to mute the mutant genes responsible for causing patients’ nervous systems to gradually go haywire.

If early trial results show a reduction in levels of the harmful proteins believed to cause these diseases, then larger trials are likely to follow providing a new path to fight life-stealing conditions that, for all of human history, have remained untouchable by medicine.

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While positive results are far from certain, Ionis already has a serious proof-of-concept in Spinraza, a drug approved late last year that uses a similar but not identical approach to successfully treat a neurological condition that kills one in 1,000 children before they reach their second birthdays.

The big deal here is that Ionis has been able to show success working on the far side of the blood-brain barrier, a protective shield of sorts that automatically filters out most drugs injected into the bloodstream, making targets in the brain and spine extremely difficult to hit.

So, if early-phase results, the first of which are expected in January, show that these DNA drugs — formally called “antisense oligonucleotides” — can reduce harmful proteins in nerve cells, well, that will be a very big deal indeed, especially because Spinraza has already proven that Ionis chemists have found ways to make these drugs last long enough in patients’ systems to create viable long-term treatments.

It’s quite a moment on the horizon, given that, just a decade ago, nobody thought this approach could work.

Well, almost nobody.

Dr. Richard Smith, a local neurologist and director of the Center for Neurologic Study in La Jolla, explained that the difficulty, the point that has drawn the most skepticism form peers, has always been drug delivery. The blood-brain barrier requires these drugs to be injected directly into the cerebrospinal fluid, and most thought such an approach would result in drugs simply floating around doing nothing.

“Everyone thought that, even if you put it directly in the spinal fluid, nerve cells wouldn’t take them up,” Smith said.

But Smith, who did pioneering work in the use of interferon to treat neurologic disease and who spent much of his career treating patients with Lou Gehrig’s disease, which scientists call amyotrophic lateral sclerosis or ALS, said he had an intuitive feeling that these drugs, these tiny pieces of DNA, might surprise everyone.

He approached high-flying UC San Diego neurobiologist Don Cleveland, a researcher known foundational work mapping the mechanisms of neuron growth and protein production. Smith recalls that first meeting with Cleveland as a bit of a roller coaster ride.

“I think this is pretty much a direct quote. He said it was “the looniest idea he’d ever heard,” Smith said.

There was a pause, and Smith said he figured he’d be accused of wasting Cleveland’s time.

“Then he said with the greatest enthusiasm, ‘let’s do it!” Smith said.

They approached Frank Bennett, now senior vice president of research at Ionis, and pitched the idea. With a doctorate in pharmacology, Bennett knew the challenges involved in getting tiny pieces of DNA to enter nerve cells and was skeptical but still open to Cleveland and Smith’s ideas even though Ionis, previously known as Isis Pharmaceuticals, was not at the time involved with trying to use the technology on neurological diseases.

The key, Bennett said, was that Smith and Cleveland had identified a specific type of “messenger” ribonucleic acid or “m-RNA” that could, theoretically, be blocked by a designer DNA drug.

“I listened to the idea and said, ‘it’s interesting and attractive because we finally have a target we can go after,” Bennett said.

Ionis agreed to make a batch of drug candidates for further research, and when that first batch didn’t pan out, agreed to do a second round of 80 candidates. Smith described this progression with wonder in his voice. To receive so much commitment on such a long shot, he said, is unheard of, especially because most of Ionis’ work at the time was in cancer.

“I mean, they were a cancer company, so for them to make 80 different molecules for us to try, and then another 80 after that, it was just remarkable,” Smith said.

The key to early success in animals that has allowed further work in human patients has been the ability to prove that these drugs do get sucked in by nerve cells and that chemical wizardry performed in Ionis’s huge labs has made the drug stable and durable enough to last long enough to bond with passing mRNA strands.

The efficacy, Cleveland said, has amazed everyone.

“We don’t get two hours of efficacy. We don’t get two to three days. We don’t get two or three weeks. We get three or four months. The drug lasts a really long time,” Cleveland said.

That means that patients could theoretically come in a few times a year, get a shot in the spine, and go home.

“That would be more like going to the dentist. You don’t necessarily look forward to it, but you do it,” Cleveland said.

This approach has recently produced startling results with spinal muscular atrophy, Spinraza’s successful target. Lack of a key protein causes the motor neurons in patients’ spinal cords to whither and die, but, using a specially-designed antisense oligonucleotide, researchers have been able to fix a critical error in messenger RNA, allowing a very similar substitute protein to be produced.

Approved by the U.S. Food and Drug Administration in December after its development by Ionis and a team at Cold Spring Harbor Laboratory in New York, the drug has already been delivered to hundreds of children and adults and, in many cases, has dramatically reversed nerve damage.

“Now they have kids who are walking, kids who never could move, for those families, it’s a miracle,” Cleveland said.

These results, coupled with the trials that are about to show results, caused a fair bit of excitement at the recent annual meeting of the American Neurological Association recently.

Gathering in a large meeting room at the Sheraton San Diego hotel, extremely sharp minds from all over the world listened as Cleveland explained the trials underway.

It’s a big change, Cleveland said, from where things were at just a few years ago.

“I wouldn’t have even been invited to speak to a meeting like that, because no one thought it could work. We’ve really gone from total skepticism and outright criticism to a feeling that these drugs are just obvious and inevitable,” Cleveland said.

After hearing Cleveland speak, Dr. Craig Blackstone, senior investigator in the cell biology section at the National Institute of Neurological Disorders and Stroke, said Cleveland and Smith get lots of credit for their sheer tenacity.

“They’re the ones who really moved things forward in terms of convincing Ionis that they should do this. They’ve shown lots of people that there’s a real possibility that this approach is going to be effective,” Blackstone said.

So, are similar results coming for Huntington’s and ALS given that they use the same designer DNA approach in a different way?

At the moment, all results are still blinded, and researchers don’t know what’s coming.

It’s important to note that, while all of the estimated 30,000 Americans living with Huntington’s could potentially be affected, it is not yet known what a reduction of harmful protein levels will mean for these patients. And, for ALS, these drugs will affect only the “familial” form of the disease, which is estimated to affect only 5 percent to 10 percent of all cases. The vast majority of ALS cases are termed “sporadic” and their cause has not been traced to specific genetic mutations.

Still, a detectable drop in the harmful proteins that cause ALS or Huntington’s, Cleveland said, even if it does not cause a meaningful reversal in symptoms, will be good enough to justify larger and longer trials where more significant results would be more likely.

“If we can shut off the bad gene, it’s just really likely that will have a big effect on disease,” Cleveland said. “That would be very exciting.”

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paul.sisson@sduniontribune.com

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