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The new research is not yet peer-reviewed nor published.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:
- 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.
- 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:
- 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.
- 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.
- 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.
PSP Blog 
Hi there Dr. Golbe,
My mom insisted that I leave a comment on your blog… and who am I to refuse such a strong woman’s request?
About six months ago, I was desperately searching for some sort of explanation for the sudden and severe changes my mom had been experiencing over the previous 1-2 years. While brainstorming with my husband (an MS2) about what could explain her frequent falls, extreme photophobia, and changes in voice and emotion, he mentioned PSP as a possible cause.
In a desperate attempt to understand this rare condition that seemed to match my mom so closely, I dove into the published literature on PSP. In the process, I stumbled upon CurePSP and then discovered your blog. Just one day later, we received shocking news: our neighbor (one of two individuals in our neighborhood diagnosed with Parkinson’s) had passed away, and his autopsy revealed he had been misdiagnosed. He had PSP.
Devastated, I spent the following months dedicating every spare moment to learning about PSP, requesting referrals, scheduling tests, attending every appointment with my mom, and dissecting each result and lab value. I was determined to prevent her from facing the same long and painful journey of misdiagnosis that so many others have endured. During this time, I have felt nearly every emotion imaginable:
I’ve felt certain my mom had PSP.
I’ve felt self-doubt when specialists dismissed “unremarkable” results that, to me, seemed remarkable.
I’ve felt encouraged watching my mom develop self-advocacy skills and fight to be heard.
I’ve felt angry when doctors insisted she couldn’t have PSP because she still retained some vertical gaze and neck movement… ignoring our comments of how stiff and still she has become, how she hardly blinks, how her eye veer to the side when she looks upward, how she spends her days in dark rooms, and struggles to find a sauce in the fridge if it’s moved one shelf higher.
I’ve felt deep joy for the time I’ve had with her and fulfillment as she’s turned to me for help, answers, and hope.
I’ve felt sorrow for those who have no one to advocate for them, who are brushed aside like so many have tried to do to my mom.
I’ve felt defeated. I’ve felt hopeful. I’ve grieved. I’ve celebrated. I’ve wept. And I’ve laughed with my family as we try to find light throughout this dark journey.
Then, just three days ago, I felt heartbroken for my mom as we finally received the diagnosis I had long suspected. It was a bittersweet moment… she finally had an answer to her question of why everything had been changing so quickly. She didn’t react outwardly when she was told she had PSP (I was almost grateful for the apathy she has developed toward some aspects of life). But I know my mom, and I know that deep inside, she was terrified.
In that moment, I felt devastated… devastated that I couldn’t fix this for her, that I couldn’t take it away. All I could do was try to keep bringing her any glimmer of light and hope I could, and remind her that she is still her: a mother, a wife, a loyal friend. A human – not a disease.
Throughout this journey, I’ve turned to many tools to cope with my frustration, fear, and anticipatory grief. One of them has been poetry. I’ve written several poems that I’ve read aloud to my mom and watched as the words seemed to bring her strength and hope.
As you know, hope is powerful, and to receive hope in dark times is a gift. So, I write this long and overly dramatic message simply to say thank you. Your blog has not only been an invaluable source of information for me and others I’ve shared it with, but it has also given my mom and my family the beautiful gift of hope.
And just days ago, when we received confirmation of her diagnosis, we were ready to begin exploring clinical trials. But before doing so, I took a moment to revisit your blog. It was almost overwhelming to see your recent posts. They were so full of hope, and so perfectly timed. I was able to share them with my mom, and in that moment, I saw a small glimmer of light return to her eyes. There are no words to describe the gratitude I felt as I watched her receive something to fight for.
So, Dr. Golbe, thank you. Not only for the hope your recent posts have brought to our family, but for your lifelong advocacy for those living with PSP. Thank you for standing up for the individuals and families who are navigating this devastating diagnosis, and for those yet to face it, who will someday sit under fluorescent lights and hear the words that change everything.
As I mentioned, my mom gains great strength from the poems I write for her. After reading your post titled “Proof of principle and cause for hope,” I was inspired to write her a new one. She insisted I share it here so you could read it too (I think it may be one of her new favorites).
Dear Delaney:
Thank you so much for sharing your feelings in this way. The poem is wonderful and I’ve turned it into a post on its own as well as leaving it here in the Comments section. I know it will inspire many others to join your mother in keeping up the fight. It certainly inspires me to continue what I’m doing.
Yours,
Dr. Golbe
Proof of Principle: a Valley of Hope
“Proof of principle: a cause for hope”
A reason to fight; to stay afloat
They say, “life is a journey,”
that it’s long and uncertain.
Your path twists, then attacks you, all attempts to dishearten.
Then all of a sudden,
you’re falling and flailing as you crash and collide
into deep, daunting valleys,
canyons so dismal and wide.
You’re flanked by trough walls that trap you within and torment your mind.
But you don’t listen to the echoes, whispering lies to deceive you;
you know you aren’t lost, you know you’ll break through.
So you take a deep breath, drawing on bravery from within,
You refuse to surrender, to give up, to give in.
You know fear always lingers,
but courage always wins.
You start stumbling forward, slowly gaining ground.
The trek leaves you breathless; gravity beats you down.
You feel the weight of the world while the battle rages on,
But the fire within you continues to burn.
Your small, sluggish steps start to widen with ease,
It’s the fight of your life, but you begin to break free.
And, alas, you continue on your expedition of existence;
you push through, stumble forward, stagger onward, with persistence.
Until suddenly you see it, it’s in the distance, growing near.
You’ve made it out of the valley, rounded the slope – you’re free from fear.
And as you begin to catch your breath, you reflect on your trials;
the valley you conquered, despite slopes that continued for miles.
Most forget that the valley was formed over millions of years.
Brutalized by the elements, she now shapes the frontier.
The formidable sight was once a simple mound of mass,
just rugged terrain standing strong, firm, and vast.
Yes, time played its tricks, and nature dealt her cruel hand,
and the river came crashing, plundering through the land.
It cut through the valley, weathering her down,
eroding her body, leaving only slopes that had cradled the mound.
The river was violent, bringing pain, bringing change,
but as the centuries passed, the valley earned her triumphant name.
And despite the cruel torture the river unleashed,
the valley became a symbol of struggle on the journey to peace.
Proof of principle: a valley of hope.
Through trials come victory; your fight keeps you afloat.
You’ll voyage through valleys, hike mountains, climb slopes.
You’ll venture to the top, gaining strength as you cope.
And when you finally reach the peak, you’ll look back at how you’ve grown;
you’ll see that, despite climbing solo, you were never alone.
Because just like the valley, you’ve persevered through endurance and loss,
learning lessons that make you, shape you, and give you reason to pause.
To look back at your life, at each valley and slope that you’ve met,
where you’ll be awe-struck by your resilience on the journey you’ll never regret.