Tag Archives: antisense oligonucleotide

Anti-sense makes sense

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Today’s New York Times had a human interest story about people with a rare, genetic form of amyotrophic lateral sclerosis (ALS; Lou Gehrig disease) who are benefiting from a drug called tofersen (brand name, Qalsody). It was approved for clinical use in the US in 2023 and in Europe in 2024.  The drug slows the progression of that rare form of ALS by about two-thirds, a phenomenal degree of efficacy.  Today’s story was not news, just a heart-warming a review of the experiences of a few of the people benefiting.

Tofersen is a member of a drug class called “anti-sense oligonucleotides” (ASOs).  If that sounds familiar, it’s because several other drugs with the same mechanism are being developed for PSP.  ASO’s interfere with the ability of one’s cells to manufacture a specific protein.  In the case of PSP, that protein is tau, and for ALS, it’s superoxide dismutase-1 (SOD-1).  The FDA approval and the NY Times story pertain only to the 1-2% of ALS sufferers with an inherited mutation in the SOD-1 gene.  However, a 30-subject, non-blinded trial of tofersen in people with ALS without an SOD-1 mutation (that is, the vast majority) is in progress at Washington University in St. Louis, under the direction of Dr. Timothy Miller and colleagues, the drug’s original discoverers.   That trial is scheduled to end in 2028.

As far as PSP is concerned, the ASO furthest along the pipeline is NIO-752, from Novartis.That Phase 3 trial is scheduled to start this month (May 2026) with 300 patients with non-familial PSP (as for ALS, the vast majority). 

Should we expect a two-thirds slowing of progression, as in ALS with SOD-1 mutations?  Probably not, for two reasons:

  1. There’s no single mutation producing abnormal tau protein in the vast majority of people with PSP. 
  2. ASOs are large molecules – to large to cross the blood-brain barrier.  So, they are injected directly into the spinal fluid using the same procedure a diagnostic spinal tap.  ALS is a disease mostly of the spinal cord, which is close to the injection site and only a fraction of an inch in diameter, so tofersen can easily soak into the cord’s full thickness. PSP, on the other hand, is mostly a disease of the brain, where a drug must penetrate a longer distance and into a much larger mass of tissue.  It has been shown to do so in monkeys, but our large human brains may be a different story.

Despite those caveats, I’m optimistic because even if PSP derives only half of the benefit enjoyed by this genetic form of ALS, it will be a huge advance. Scientists call this “proof of principle.” That means that the general idea has been found to make sense in a similar situation.

The list of centers slated to participate in the NIO-752 trial has not been announced, so if you’re interested, keep an eye on www.clinicaltrials.gov, www.curepsp.org or this blog. Before you volunteer, keep in mind that several other promising trials for PSP will be starting over the next few months. Check those same three sources for info on those.

(Disclosure: I’ve done consulting for Novartis, but none since 2023, and I have no financial interest in the company.)

Proof of principle and cause for hope

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The gene therapy company uniQure announced today that its has succeeded in slowing the rate of progression of early-stage Huntington’s disease (HD) by 75 percent.  Although the specific treatment would not work for PSP, the general principle successful in HD could be relevant to all neurodegenerative diseases.

The new research is not yet peer-reviewed nor published.  In writing this post, I used information from the company’s press release,  a news article from the BBC, and Old Reliable, ClinicalTrials.gov.

Unlike PSP, HD is a purely genetic disease.  It works on an autosomal dominant mechanism with full penetrance, which means that anyone inheriting one copy of the disease-causing version of the relevant gene from either parent will develop the disease.  The gene’s technical name is IT15 and it encodes a protein called huntingtin or HTT (notice the “-in” ending indicating a protein).  The gene defect is extra copies of a span of the three nucleotides C, A, and G. This “CAG repeat expansion” directs the cell’s protein factories (the ribosomes) to build into the HTT protein an excessively long string of the amino acid glutamine.  The normal span is 7 to 35 CAG repeats, but in people with HD, one of the person’s IT15 genes has at least 36 repeats. In people with HD, the normal version of the IT15 gene continues to make normal HTT, which means that half of their HTT is normal and half isn’t. The new treatment suppresses the brain’s production of the abnormal half.

Here’s how the trial worked: The researchers started with a kind of virus routinely used in research called AAV, which readily enters brain cells but by itself causes no harm.  They made short stretches of DNA designed to encode a type of micro-RNA corresponding to the abnormal HTT protein.  They inserted that DNA into the viruses and dubbed the result, “AMT-130.” In a 12-18-hour neurosurgical procedure, they injected the AMT-130 viruses into the caudate and putamen, the parts of the brain where HD does its main damage. The viruses released their DNA into the brain cells, which started transcribing it into RNA.  In this case the RNA was actually a “microRNA” designed to bind and disable the cells’ own abnormal RNA that would have gone on to be translated into abnormal HTT protein.   

In that way, the researchers hoped to reduce the cells’ production of abnormal HTT protein.

The trial included 29 people with HD at four study sites (Two in Warsaw, Poland and one each in London, UK and Cardiff, Wales.) Seventeen of the participants received a high dose of the virus, 12 received a low dose and all were observed for 3 years.  They were examined using the standard Unified Huntington’s Rating Scale (UHRS) and other measures of neurological function as well as spinal fluid sampling to measure levels of proteins associated with neurodegeneration.  As a control group, the trial used records of people with HD from an unrelated study of the natural history of the disease called “Enroll-HD.”

The result in the high-dose group was far better than anyone dreamed of. 

The “primary outcome measure,” the rate of worsening in the UHRS, was only 25 percent of that of similar patients from the control group.  Subsidiary measures of clinical efficacy gave similar or even better results.  Levels of neurofilament light chain (NfL), a protein released into the spinal fluid by degenerating brain cells, actually declined, while increasing in the control population. 

The low-dose group gave much less impressive results, which in a way is good because it suggests that the improvement was actually from the treatment rather than from some statistical fluke.

So, is this relevant to PSP?  Yes and no.

It’s relevant to PSP because:

  1. PSP and HD are both neurodegenerative diseases with an abnormally aggregating protein playing a critical but incompletely understood role in the loss of brain cells: tau for PSP, huntingtin (HTT) for HD.
  2. The anti-sense oligonucleotide treatment presently under development in PSP, NIO-752, works by the same principle as the AMT-130 virus.  But it’s injected into the spinal fluid and engages the tau messenger RNA directly, whereas AMT-130 releases DNA, which encodes RNA acting as the equivalent of an anti-sense oligonucleotide.

It’s not so relevant to PSP because:

  1. The tau protein aggregating in PSP is not defective from a genetic standpoint.  Yes, it’s misbehaving, but as far as we know, PSP has no common, specific, mutated form of the tau gene that could make its RNA susceptible to a targeted attack like that provided by AMT-130.  Rather, the misbehavior of tau in PSP is caused by other abnormalities in the brain cells resulting from the cumulative effect of multiple mild genetic mutations, probably along with some sort of toxic environmental exposure. 
  2. The ASO under development for PSP simply reduces the production of normal tau, and since tau has essential functions in the healthy brain, we would not want to completely eliminate its production as AMT-130 could potentially do for HTT in HD.  This means that any benefit provided by the ASO in PSP would have to be moderate at best.
  3. The damage in early HD (the stage recruited by this trial) is almost entirely in the caudate and putamen, the targets of the injections.  But in PSP, by the time a patient is diagnosed, the damage has involved many more than just two areas on each side of the brain.  This would make injecting all the involved areas extremely difficult.

Despite these reservations, the news is good for PSP because like the monoclonal anti-beta-amyloid antibodies for Alzheimer’s disease, AMT-130 sets a precedent for slowing the course of a neurodegenerative disease by attacking an aggregating protein.  But unlike the AD results, the patients receiving AMT-130 for HD suffered only mild side effects and enjoyed a dramatic benefit.

Even if this technique can’t help PSP because its tau is not genetically defective, other proteins are likely to be mutated in at least a few people with PSP.  We do know of 22 genes with some sort of genetically-related defect, but we don’t know if any are encoded into defective proteins like the HD mutation is. 

But we can hope that before too long, there will be diagnostic markers to detect PSP before it spreads beyond two or three small brain areas; and the results of genetic testing in a lone individual with PSP will allow their neurologist to order up a cocktail of injectable gene therapies to fit their own combination of mild gene mutations.  We can dream.

NIO752 update

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Today reader RW posted a comment asking about the status of the NIO752 trial. I thought my answer was so, SO well-crafted and informative that I just had to promote it from a comment response to a full blog post, and here it is:


RW:

First, for the benefit of your fellow readers, NIO752 is the anti-sense oligonucleotide from Novartis. An ASO is a short span of RNA injected into the spinal fluid space. In this case, the injections are given four times: every three months for a year. The drug reduces production of tau at its source — where its gene is transcribed into protein. In my opinion, it’s more likely to work against PSP than any other past or current experimental drug. However, the need for the spinal injections could limit its appeal, especially if one or more of the oral (i.e., more convenient) drugs currently in more advanced stages of clinical testing reach the market first.
The Phase 1 NIO752 trial ended a month or so ago and Novartis, apparently, is still crunching the numbers. It’s typical for that to take 2 or 3 months, so I wouldn’t infer anything from it. Keep in mind that this was only a Phase 1 trial, powered to assess safety, not efficacy. I haven’t heard anything through the grapevine about major safety problems during the trial, but you never know what the actual data might show or how the company might react in terms of continuing to advance the drug into a Phase 2 trial.
LG