The past month has been a hot time for therapeutic research in prion disease.  Two new studies have announced positive results in animal models and have proposed that these treatments may eventually be evaluated for possible use in humans.  The media coverage hasn’t always been as good as the science, so here’s the lowdown.

Above: The new studies on astemizole and anle138b both relied on high-throughput screening using tools like these 96-well plates to test thousands of compounds.  High-throughput screening used to be exclusive to pharmaceutical companies, but today more and more academic research institutions are using it too, helping to discover potential ways to treat rare diseases like CJD, FFI and GSS.

astemizole

The first announcement concerned a drug called astemizole.  Scientists at Scripps Florida discovered that this drug can increase reduce the amount of prion protein produced by cells, potentially delaying disease [Karapetyan & Sferrazza 2013].  Astemizole used to be an FDA-approved antihistamine.  It was later pulled from the market due to very rare cardiac complications.  On balance, though, it’s actually got a good safety record – the adverse effects were deemed enough to make the drug obsolete in the face of newer and better antihistamines developed in the 1990s, but are not common enough to preclude its use in this case.  After all, prion disease is a lot more serious than seasonal allergies.

So the astemizole finding could turn out to be promising.  But Scripps’ own press release described the finding as the “first potentially effective therapy for human prion disease.”   Whoa!  Let’s back up a minute here.  In the mouse model used in this study, astemizole only delayed onset of disease by 4%, and the effect was of borderline statistical significance (p = .06).  Further work will be needed to even know for sure that the effect is real.  Moreover, several other drugs and supplements have delayed disease by more than 4% in animal models – statins, curcumin, memantine, rapamycin and Scutellaria lateriflora to name a few.  Measurable effects in an animal model don’t necessarily imply an “effective therapy” for humans.  Moreover, both astemizole and tacrolimus (a second candidate drug identified in the Scripps study), had already been investigated as potential treatments for prion disease years ago [Kocisko 2003, Bertsch 2005, Mukherjee 2010].

Future work may yet show that astemizole is indeed effective and could be brought back onto the U.S. market.  For now it’s too early to say.  But actually, what’s most exciting about the Scripps study is not astemizole in particular, but the new assay that the scientists used to discover astemizole’s effects.

Most past efforts at discovering drugs for prion disease have focused on trying to prevent the conversion of healthy prion protein to diseased prion protein.  That’s a dodgy business because prion diseases come in several different strains – fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, and multiple subtypes of Creutzfeldt-Jakob Disease – and so far all of the treatments that target prion conversion have found effects to be strain-specific even among mouse prion strains, making it a longshot that they’ll work in human prion strains.  In contrast, the Scripps researchers focused on reducing the amount of healthy prion protein produced by cells to begin with.  That’s a more universal approach, because all prion strains rely on having healthy prion protein available in order to convert it and spread throughout the brain.  We’ve argued that reducing prion protein levels is the best therapeutic strategy, and the Scripps study is evidence that other scientists are starting to think this way as well.  Hopefully this will lead to more exciting therapeutic leads in the future.  To learn more about the Scripps study and why we think it’s good news – but definitely not a “first potentially effective therapy” – read our review of the study on CureFFI.org.

anle138b

The second piece of news is the discovery of a completely new molecule dubbed anle138b [Wagner 2013 (full text here)].  A group of scientists in Germany had been working on this and related compounds for several years.  They patented anle138b back in 2009 and published some related results in 2011 [Geissen 2011, Leidel 2011] but were apparently waiting to finish more experiments before publishing their results on anle138b last month.

The researchers provided a variety of biochemical evidence to argue that anle138b inhibits the formation of infectious particles composed of multiple prion protein molecules, and that its effects appear to be equal across multiple strains of prions.  They also tested it in a Parkinson’s disease mouse model and found evidence of therapeutic effects, suggesting the effects might be applicable to more than one protein-folding neurodegenerative disease.  But the most impressive part of the study is the survival evidence from prion-infected mice.  When mice were treated with a large dose of this compound starting right at the beginning of prion infection, it nearly doubled their survival time.  Even more impressively, it extended survival by about 30% even when it was administered pretty late in prion infection.

That sort of effect is almost unprecedented.  As we’ve pointed out, similarly large effects late in disease were seen years ago for pentosan polysulfate, which nevertheless turned out not to work in humans [Bone 2008, Tsuboi 2009].  For that reason, it’s too early to get excited that anle138b will necessarily prove effective.  Still, it has a lot going for it: anle138b can be taken orally and find its way into the brain, whereas pentosan polysulfate had to be infused directly into the brain, which led to some nasty complications.  And though it’s too early to say, the evidence so far suggests anle138b’s effects might be fairly consistent across different prion strains.

As a novel molecule, anle138b is still a long ways from becoming a drug – more work will be needed to demonstrate its safety and efficacy before it can advance to a clinical trial in humans.  And it didn’t prevent or reverse disease, only delay it, so even at best it won’t be a cure.  Still, it is the most promising candidate developed so far.  Therefore it’s been slightly surprising that it has received almost no media coverage, especially when compared to astemizole.  On the other hand, the little coverage we have seen has been pretty inflated.  SciTechDaily reported that anle138b “Slows Down the Onset and Progression of Parkinson’s Disease”.  That statement needs two additional very important words: “in mice.”

To learn more about the details of anle138b, check out our review on CureFFI.org.  It’s too early to know if it will prove effective, but this compound is nevertheless exciting news, and another sign that progress is being made.

This week we’ve had the pleasure of attending the 2013 Genomes, Environments and Traits (GET) conference put on by the Personal Genome Project here in Boston.  It’s been a fascinating chance to reflect, both as scientists and patients, on the role of genomics in society.

The better part of the morning sessions yesterday were spent discussing the sticky issues of how much it is appropriate – or possible – to involve patients in research and inform them about the results of research and even clinical work being done on their genomes.  The new ‘ome’ of the day was the incidentalome, the set of incidental findings that come up when you do genotyping or sequencing on a person.  Steve Scherer estimated that 50% of clinically relevant findings from genomics are incidental, meaning unrelated to the condition for which the patient was originally referred.  The question of how, and even whether, such findings should be returned to patients is hugely controversial.  Robert Green and Heidi Rehm discussed the new set of recommendations they had helped to produce, which in essence say that patients should receive all clinically relevant findings, incidental or otherwise.  The GET conference was by far the most pro-genomics group of people we’ve ever been in a room with, and so the audience was wholly on board, but Green noted that another group is right now preparing a scathing retort to the recommendations, claiming that returning incidental findings takes away patient autonomy.

Why? After all, Green pointed out that in all other medical tests – X-rays for example – the reporting of incidental findings is mandatory.  Amidst all the supposed controversy, no one has presented a good reason why genomics should be any different.  What’s really different, we think, is simply that genomics is new and scary, while people have long been used to X-rays.  Just a year and a half ago we, too, were terrified of the genome, but we’ve changed our lives based on what we learned.  Genomics is the future, and it’s a future where people can take action.

The tragic Boston marathon bombings last week were a sobering reminder that not everyone gets 20 years advance warning that their life is in danger.  Danger can strike at any time.  We are renewedly grateful to live in an era where information wants to be free, where genomics makes it possible to glimpse – and change – the future.

On the subject of human violence, one of the real treats of the conference was getting to see Stephen Pinker speak.  It was only marginally related to genomics, but he is such a fantastic speaker that everyone was riveted:

Conversation: Steven Pinker on Decline of Human Violence from The Personal Genome Project on FORA.tv

But above all, the singular highlight of the conference was getting to see HDBuzz‘s Jeff Carroll and Ed Wild speak.  Jeff Carroll’s story is uplifting and inspiring: he was 19 years old and serving in the U.S. military in Kosovo when he learned that his mom had Huntington’s Disease.  He got tested, found that he had the mutant allele, went back to school, and is now a scientist researching Huntington’s.  He’s a role model for us, and he paved our way in more than one sense – he used to work in our lab at MGH, and his brilliance and dedication convinced his colleagues of the value of hiring scientists with a personal motivation to find a cure.

Radical Participant Access to Health Research Data from The Personal Genome Project on FORA.tv

Carroll and Wild spoke about HDBuzz, their project that seeks to educate patients on the results and significance of scientific research in Huntintgon’s Disease.  ”A scientific work is not complete until it has been understood by those who need it most”, said Jeff.  Both spoke beautifully about the relationship between science and hope.  Showing an image of natural gas being flared at an oil rig (circa 11:00 in the above video), Ed said:

Hope is an automatic by-product of scientific research, and we have a forced choice as scientists: we can either let it evaporate uselessly into the air by not engaging with the public whom we serve, or, with a small amount of reprocessing, we can turn it into something incredibly useful, that no other thing can achieve.

This is what motivates their effort to educate the public about scientific progress through HDBuzz.  The goal is to provide “substantive hope”: not reassurances that everything will just work out, nor blind faith that science will cure all, but rather hope grounded in real knowledge of the progress being made.  That’s a hope we can believe in.

The Rare Disease Challenge voting ended at 1:00 am this morning, with the Rett Syndrome team taking 1st place with 15,607 votes.  Our team placed 4th out of 10, with 1,414 votes:

We’d like to extend a huge thanks to everyone who voted for us – repeatedly!  It’s a lot to ask to have people remember to log on and vote every day, yet by the end we found that over a hundred people were voting for us every day, which is pretty awesome.  We really appreciate all of your support and help in getting the word out to your extended circles.

Though we didn’t end up winning 1st place for the $10,000 cash prize, these were a really great couple of weeks nonetheless.  This competition was a good motivation to step up our outreach efforts, and it paid off.  Through Facebook we reached out and met several other families affected by genetic prion disease, and we are really grateful to be able to connect with people in the same boat!  Even besides the other families, we just met a lot of really wonderful people who wanted to support us – we tripled our number of Facebook Likes, received donations from new folks, and kind words and emails from all around.  Our story was told on MIT’s CoLab Radio and in Swarthmore’s Daily Gazette, leading to people we had never met getting in touch to tell us they are excited about what we’re doing!

Rare Disease Challenge aside, we are moving forward with our research goals and are well on our way to meeting our fundraising goal for this month – donate here if you haven’t yet (thank you!)

By the way – don’t miss the interesting new posts at CureFFI.org.  Those of you who’ve heard us expound on the value of personal genomics (and aren’t tired of hearing about it yet!) will enjoy our post on our experience with 23andMe (preview: we strongly recommend it).  And if you’re in the mood for a brainteaser and reminiscing about the days you used to read Parade Magazine, check out fatal familial insomnia and the boy girl paradox.

Good news: Facebook voting for the Rare Disease Challenge is open! Vote for us here!  update: you can vote every 24 hours.  please do!  If we win we’ll be awarded $10,000 in seed money to get started on our research goals.  This early money will be really helpful for us in getting preliminary results that will help us compete for grants in the near future.

Our proposal, submitted late last year with a research team led by George Carlson, is to convert a sample of Sonia’s skin cells to induced pluripotent stem cells and use ‘molecular scissors’ called zinc finger nucleases to create a batch of them that is genetically identical except for the single DNA base mutation that causes fatal familial insomnia.  With this tight experimental control in hand, we can study the appearance and gene expression of the cells in great detail to see what is going wrong in the FFI cells, and eventually be able to screen for drugs that make the FFI cells act more like the healthy ‘corrected’ cells.

Surprisingly, according to the list of winners we weren’t the only fatal familial insomnia project in the competition!  Christina Chao, we Googled you and couldn’t find you – if you see this drop us a line to let us know who you are – we should combine forces!

We’re already a Gold winner and will get some of the donated biotech services – see the full press release and list of winners - but we need your vote to win the cash prize.  Vote for us now!

Good news: Prion Alliance and our research team led by George Carlson have been selected as finalists in the Rare Disease Challenge!  Rare Genomics is expected to make an official announcement at Rare Disease Day in D.C. today, kicking off Facebook voting to determine the final winner of the $10,000 prize!  Check back later today to learn how to vote for us to win.  In the meantime, if you haven’t yet, don’t forget to like us on Facebook.

2013 is off to a good start.  Here are a few updates from the past few weeks:

• We received the match for all of your generous December donations, and more donations have continued to come in throughout January pushing us above $12,000 total.  Thanks everyone!
• We’ve added our story to the Prion Alliance website.  It proved to be a surprisingly difficult story to actually sit down and write, but now we’ve finally got something down on the page so people know why we started all of this.
• We are now able to accept recurring monthly donations via PayPal.  It’s slightly trickier to set up with Amazon, so we haven’t gotten around to that yet, but if you want to donate each month through Amazon let us know and we’ll make it a priority!
• This month we have been hard at work understanding the science of modeling human diseases using adult skin cells reprogrammed to neurons and of editing genomes using the ‘molecular scissors’ known as TALENs and ZFNs.  This is amazing stuff and we are excited to put it into action for studying prion diseases!

The results of our end-of-the-year push are in, and we raised a total of $5,700 in December – that’s $11,400 with our 1:1 match.  Amazing!  Thank you so much to everyone who contributed!  You have blown us away with your generosity.  Thanks to your help, we are now well on our way to being able to fund some early efforts on our stem cell project for the Rare Disease Challenge and more broadly being able to kick off some of our research goals.  This early money is going to be crucial in helping us do enough to position ourselves competitively for larger grants over the next several months.

We’re a bit behind on thank yous and receipts but we’ll catch up in the next couple of days.    In the meantime, we want to let you know we’re starting the new year on a note of unbridled optimism and that we are incredibly grateful for all of your support.

2012 was an incredible year. We got Sonia’s genetic test results in December 2011 – just over a year ago.  By January 2012 we had embarked on our new adventure of becoming scientists, had enrolled in night classes and started CureFFI.org.  We soon found new jobs in science (Sonia in April, Eric in July), founded Prion Alliance (June), got 501(c)(3) status (October), and in just the past month we’ve started a new research project with a new team and raised $11,400 in our first month of fundraising thanks to generous people like you.

Here’s to 2013: an even awesomer year. Thanks for being with us.

Exciting news: we’ve now raised over $4,000 – that’s $8,000 with our 1:1 match.  We’re 40% of the way to our goal of matching $10,000 by the end of the year.  Our hearts are full of gratitude toward everyone who has chipped in – many of you have been incredibly generous, and we don’t know how to thank you enough.

Today is the last day of 2012 that we’ll be able to receive snail mail, but we’ve worked it out that if any checks trickle in during January that are postmarked Dec 31 or earlier, we’ll be able to apply the match.  In the meantime, online donations will continue to be matched 1:1 for the next three days – and by the way, we’ve added Google Wallet as another payment method.

As a treat to reward all of your generosity, we’d now like to share what we think may be the funniest thing that happened in 2012.  The backstory is this: about a month ago, many of you got an email from us announcing that we’d launched Prion Alliance and asking for your support.  A few days earlier, when Sonia first sat down to start drafting that email, she tried to do so on Swype on her Android phone while waiting outside for an MBTA train in the Boston winter.  Both the phone and her fingers were extremely cold and if you’ve ever used Swype before, you know how it can suddenly freak out for no reason and start adding all kinds of random words you didn’t even type, and then when you go to hit backspace it gets even more excited and interprets the backspaces as whole new words.  On that fateful day, this series of events gave rise to the following text:

 Dear friends and family,
As most of you know, Eric and I learned about a year ago that I am a carrier of FFI, the genetic prion disease of which my mom died in December 2010.
Since receiving this news we jabber both been hard at work retooling in order to best address plop I r lloml lMm loololoo ml mollusk mml mml mml mmmml Mloloo LOLml lololoo ml,

If you agree with us that having a sense of humor about even the hardest things in life is awesome, then please donate, like and/or share!  Thank you!!

It has been 48 hours since we announced that donations will be matched 1:1 through Dec 31, and we’ve raised $1,970 so far – that’s $3,940 with matching – and so we’re about 20% of the way to our goal for the end of the year.  Friends, we are humbled by the outpouring of support and encouragement we’ve received from everyone over the past several days, evident both in these donations and in the outpouring of kind words we’ve received from all corners.  Thank you so much.

Here is a quick token of our optimism for the future:

Following the good news from earlier this week, we now have an amazing donor who will be matching your donations dollar for dollar through midnight on New Year’s Eve 2012, up to $10,000 matched (i.e. $20,000 total). Donate now before the year is over, and double your donation.

We’ve already applied the match to all the donations received in the last two weeks (thanks everyone!), and we’ll apply it to any other online donations or checks we get before year’s end.

We would love to use every cent of this opportunity, so our new ambitious goal is to use all $10,000 of match, raising $20,000 in total, by the end of the year. If we do it, we’ll already be more than halfway to our longer-term goal of $35,000 by the end of March.

The time is now: donate, and tell your friends about it too using the social media links below.