Tag Archives: Huntington’s disease

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The new research is not yet peer-reviewed nor published.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.

Bad company

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I have good news and bad news, and they’re the same piece of news.

You’ve heard of Huntington’s disease.  That’s the strongly hereditary condition that causes dementia and involuntary movements, starting at an average age of about 40 and leading to severe disability and dependency within 15 years or so.  Its most famous victim is Woody Guthrie, the folksinger/songwriter who died in 1967.  HD caused by a pathogenic variant (the word “mutation” is no longer considered appropriate) in the gene encoding the protein “huntingtin,” rendering it toxic to brain cells.

The variant in HD is a “trinucleotide repeat expansion.”   The gene has a region where the three nucleotides cytosine, adenine and guanine (CAG) are repeated multiple times.  The normal number of such repeats is less than 27.  Everyone with 40 or more repeats will develop HD and each of their children has a 50% chance of inheriting the abnormal version of the gene.  For 28 to 39 repeats, the person usually remains healthy, but the number of expansions can increase during the process of producing sperm cells or ova, putting subsequent generations at risk.  A number of other neurological diseases are caused by CAG expansions in different genes.

Huntingtin protein has several known functions in the brain, but the damage to brain cells probably is not the result of loss of any of those.  Rather, the excess number of CAG repeats encodes a an excessively long string of the amino acid glutamines. That gives the protein its toxic property, but we’re still not sure how it works or what to do about it. We do know, though, that in HD, brain cells have clumps of strands of glutamine, just as in PSP there are clumps of tau protein.

In PSP, there is no single culprit gene.  Unlike HD, PSP only very rarely runs in families and each of the 14 genetic alterations currently known to be associated with PSP confers only a slight degree of risk.  I know this looks cryptic, but here’s the current list of PSP-related genes in approximate order of discovery date: MAPT, STX6, MOBP, EIF2AK3, SLCO1A2 (two loci), DUSP10, RUNX2, LRRK2, APOE2/2 genotype, CXCR4, EGFR, GLDC, and C4A.

To this list we can now add “HTT,” the Huntington’s gene.  That’s because last month, researchers announced that they had sequenced HTT from 588 people with autopsy-proven tauopathies, including 98 with PSP, along with controls without neurodegenerative disease.  They found that while only 0.2% of the controls had at least 27 CAG repeats, for the people with PSP, the figure was 3.2% and for those with corticobasal degeneration, 2.7%.  Keep in mind that in only a small fraction of those 3.2% will the number of CAG repeats expand far enough into the toxic range to pose a risk to the children or grandchildren. 

The paper’s first author is Dr. Sergio Pérez-Oliveira and the senior author is Dr. Victoria Álvarez, both geneticists at Hospital Universitario Central de Asturias, in Oviedo, Spain, along with 21 other collaborators.  The paper appeared in Brain Pathology, a well-respected journal.

So, the bad news I mentioned is a very slight increased risk of HD occurring in future generations of families with a member with PSP.  What’s the good news?  It’s that we now know of another genetic risk factor for PSP, and it’s one that we already knew a lot about, thanks to decades of research on HD.  We can compare the long list of known actions of huntingtin in the brain to the long list of actions of the 14 other PSP-related genes. More important, we can compare the known toxic action of the excessively long strings of glutamine with the list of ways in which brain cells are damaged in PSP and look there for synergistic interactions and for drug targets to disrupt such processes.

Overall, I’d say that the good news definitely outweighs the bad news, first because statistically, the bad news is only a very small risk, and the new publication doesn’t change it – it only reveals it.  But the revelation of the good news gives PSP researchers something new to sink their teeth into in their search for a prevention and cure.