The Brain Activity Map Project: short- and long-term prospects for Huntington’s disease research

The ambitious, recently announced national effort to map the circuitry of the brain and deepen understanding of its function could bring valuable new knowledge about what goes awry in Huntington’s disease-affected brains. Still, the project likely won’t have a practical impact on the search for effective treatments for years or perhaps even decades.

That’s the initial assessment from three leaders in the search for HD treatments in reaction to reports that the administration of President Barack Obama will include a multi-year, public-private-academic brain mapping project in the next federal budget. The official announcement, following Obama’s February 13 State of the Union remark about the importance of brain mapping, is expected this month, although political wrangling over the budget could cause a delay.

“Anything that teaches us about how the brain works will undoubtedly tell us something about how HD makes the brain dysfunction,” said Simon Noble, Ph.D., the director of scientific communications for CHDI Management, Inc., the firm that furthers the goals of the CHDI Foundation, Inc., the non-profit, multi-million-dollar search for HD treatments. “At the moment, it’s difficult to predict what will come out of this for HD.”

Dr. Simon Noble (photo by Gene Veritas)

Compared by the president and scientists to the $3.8 billion Human Genome Project (1990-2003), which produced a complete map of our genes, the so-called Brain Activity Map Project (BAMP) would aim to record and map the firing of the brain’s 100 billion or so neurons.

Fifteen years to a mouse study

This year marks the 20th anniversary of the discovery of the HD gene, a key step in the Human Genome Project. Initially, scientists thought that discovery would lead to potential treatments just a few years later. However, the task has proved far more complex, although a number of clinical trials are in progress or in planning, including cutting-edge gene-therapy approaches made possible by the discovery of the gene.

The scientists behind the BAMP estimate that mapping a significant part of a live mouse brain would be achieved 15 years into the project. Experiments in humans necessarily would take place years later, after testing in non-human primates.

“While the Brain Activity Map is an important and worthy project, I hope it’s irrelevant to Huntington’s disease,” Robi Blumenstein, the president of CHDI Management and a participant in an August 2012 BAMP planning session at the White House Office of Science and Technology Policy, said of the project. “Because mapping the brain is such a hard problem, the BAMP is a complex project on a long-time scale. I hope that we can deliver treatments before it becomes useful to us.”

Scientists say that the large number of neurons and the complexities of the brain, a living organ, will prove far more difficult to measure and map than the much smaller amount of inanimate material in our genes. Furthermore, because HD is a genetic disease, the Genome Project in general and specifically the discovery of the HD gene have been the major, initial breakthroughs in the search for treatments.

In 1923 one scientist referred to the connections among neurons as “impenetrable jungles where many investigators have lost themselves.” Since then, little progress has occurred. In a June 2012 article, six leading scientists identified as leaders of the BAMP likened the current technology of measuring just a few neurons at a time to watching an “HDTV program by looking just at one or a few pixels on a screen.”

Futuristic tools and techniques

“I think it’s exciting,” said George Yohrling, Ph.D., the director of medical and scientific affairs for the Huntington’s Disease Society of America. “The brain is incredibly complex, as we all know. Once we know the details of how all the different neuronal pathways and networks are talking to each other in the normal and diseased states, it could help guide us to effective treatments. In theory, all of the disease areas – Parkinson's, Alzheimer's, HD – will benefit from the successful brain mapping exercise.”

Dr. George Yohrling (CHDI photo)

However, Dr. Yohrling emphasized that the project’s ability to furnish such information will depend on the development of new research tools. At first, such tools cost enormous sums, but come down over time, he said. The first sequencing of the genome cost billions and took more than a decade, whereas today sequencing takes three weeks and will soon cost just $1,000.

"The point of the tools is key," he explained. "We see it every day in science. You can look back 10, 15 years of how we used to do certain things in the lab and think, wow, this is so archaic!"

Indeed, the BAMP scientists’ article pointed out that the project – with the gargantuan goal of imaging “every spike from every neuron” – will require an entirely new set of futuristic tools and techniques resulting from the “convergence of biotechnology and nanotechnology.” They envision such innovations as three-dimensional imaging, biologically inspired computational devices, nanoprobes, DNA molecules acting as sensors, and “small wireless microcircuits, untethered in living brains, for direct monitoring of neural activity.”

Whether nanoscience can shed light on the HD disease process is a “bit of a black box at the moment,” Dr. Noble observed. “A lot of these things will be done in mice first. Working in a human brain is extremely difficult, if not impossible. We’ll have to rely on other systems and post-mortem brains.”

If such technology becomes feasible, it might help “identify early biomarkers (signs)” of HD, Dr. Yorhling said. Biomarkers are crucial for conducting clinical trials of potential treatments.

Keeping HD in the loop

Despite the likely minimal impact of the BAMP on HD research in the short run, both CHDI and HDSA plan to carefully track its progress and seek opportunities to apply its findings and even potential inclusion in some facet of the project.

“CHDI is keeping a close eye on how these grand projects develop and always considering ways that we might be involved,” said Dr. Noble, referring to the BAMP and also a new brain-research initiative co-founded by former Rep. Patrick Kennedy known as One Mind for Research.

As Dr. Noble noted, the idea of brain mapping intersects with CHDI’s new emphasis on systems biology.

“The brain is a system, just as the body is a system,” he said. “Brain mapping is a really difficult problem, but one that’s well worth pursuing. The brain is the final frontier. It’s the least understood system in the human.”

If the BAMP came to include disease-specific mapping, HDSA would advocate for the inclusion of HD, Dr. Yohrling said. He also held out the possibility of the HD research community someday teaming with patients to carry out an HD-specific brain-mapping project, which could become feasible as the techniques advance and become accessible to more researchers.

Designing the best drug possible to defeat Huntington’s disease

With an eye on starting a clinical trial possibly as early as 2014, a scientific team in San Diego is painstakingly working to design the best drug possible to defeat Huntington’s disease.

For the past seven years, Don Cleveland, Ph.D., of the Ludwig Institute for Cancer Research at the University of California San Diego (UCSD) and Frank Bennett, Ph.D., the senior vice president for research at Isis Pharmaceuticals, Inc., have envisioned treating HD with a revolutionary gene-silencing technology that, if successful, would attack the disease at its genetic roots and perhaps even partially reverse symptoms.

Since late 2007, the UCSD and Isis teams have partnered with the CHDI Foundation, Inc., the multi-million-dollar non-profit biomedical organization dedicated to finding HD treatments. Together they aim to develop what Dr. Bennett has described as a “laser-guided missile” to prevent the damage to brain cells caused by the mutant huntingtin gene carried by HD patients.

Dr. Cleveland and Isis senior scientist Holly Kordasiewicz, Ph.D., were honored as the 2012 Researchers of the Year by the San Diego Chapter of the Huntington’s Disease Society of America (HDSA-San Diego) last night before some 500 attendees at the chapter’s twelfth annual Celebration of Hope Gala.

Isis employs a cutting-edge technology known as antisense oligonucleotides, or ASOs. DNA, the building block of life, runs our cells by telling them which proteins to make. It does so by sending messages with another molecule called messenger RNA.

As encoded by DNA, RNA has a very specific template, somewhat akin to a unique electrical outlet into which a plug can fit. RNA is known as a sense molecule, and Isis manufactures specific ASOs, artificial strands of DNA, to act as antisense molecules, the plugs that control the RNA. (Click here and here to read previous reports on the project.)

The ASOs accomplish two goals. First, they destroy the huntingtin RNA and thus prevent the production of the huntingtin protein. Second, eliminating the RNA removes it as a potential cause of other problems in the cell.

Above, some of the Isis HD team members: (left to right) Michael Oestergaard, Punit Seth, Bethany Fitzsimmons, Curt Mazur, Amy Blackley, Eric Swayze, Holly Kordasiewicz, Frank Bennett, and Marco Giorgetti (photo by Gene Veritas) (click on image to enlarge). Below, Gene Veritas inside the Isis facility in Carlsbad, CA (photo by Amy Blackley, Isis).

  

Fine-tuning, tailoring, and twiddling

Isis had originally hoped to begin a clinical trial as early as late 2010, but has delayed the project in order to perform highly important fine-tuning on several fronts.

As previously described by Dr. Bennett, Isis is searching among the many “flavors” of ASOs it makes in order to find the best match for treating HD. From an original pool of thousands, Isis has narrowed down the candidate ASOs to just five, Bennett said in a recent interview.

Isis, CHDI, and other researchers have also made significant advances on two other key research questions. First, how much of the huntingtin protein should the drug remove? So far, the scientific consensus seems to have settled on 50 percent lowering (also known as  knock-down) as the current target. However, this question will ultimately be resolved through the clinical trials.

The second, related question is trickier but could ultimately open the door to an even better drug. Because HD patients have both mutant and normal huntingtin proteins in their brain cells, should the drug lower both or just the mutant? In the early going, the ASOs did not distinguish between the “good” and “bad” proteins. However, Isis has now developed a way to knock down just the bad.

At least in theory, knock-down of just the bad is the safer approach for patients, although the project’s experiments have also surprisingly demonstrated that knock-down of both is not harmful, explained Dr. Kordasiewicz, the former head of the HD project in Dr. Cleveland’s UCSD lab.

Dr. Holly Kordasiewicz in the lab at Isis (photo by Curt Mazur of Isis)

“The decision still hasn’t been made,” she said, referring to the choice between the two types of ASOs. “It’s hedging your bets. Everything’s on the table. The chemists are doing amazing things. It would be irresponsible of us not to consider all of the options before making our final decision.”

“You never know, once you get into a human, what’s going to work,” she added. “So having everything ready to go, so you don’t have to wait three more years to develop the next thing, if one doesn’t work, you try the next.”

Using second-generation ASO technology, the Isis chemists found ways to increase both the selectivity (the ability to bind to the mutant RNA as opposed to the normal one) and the potency of the potential HD drug.

“It improves potency quite a bit,” said Punit Seth, an Isis senior research fellow in medicinal chemistry, in describing one of the key chemical innovations. “You can get anywhere from three-fold to ten-fold improvement, which then translates to lower costs in drugs and administering less [of the] drug to the patients.”

Dr. Cleveland added that these improvements would also produce a drug with potentially fewer side effects.

Eric Swayze, Ph.D., Isis’s vice president for medicinal chemistry, summed up the fine-tuning as “tailoring” and “twiddling with the number of different building blocks” that go into the ASO.

“It turns out to make a huge difference, which we didn’t really expect,” he observed.

Dr. Eric Swayze explains the function of the Isis ASOs (photo by Gene Veritas).

Patient-friendly delivery

Isis has also strived to simplify the delivery of the drug. Originally, the company planned to direct the drug into the brain using a device implanted in the abdomen and connected to a catheter running under the skin to the skull.

Now, however, the researchers aim to introduce the ASO directly into the cerebral spinal fluid (CSF, the fluid that bathes the brain) by injecting it through a quarter-sized port implanted near the rib cage, with the catheter running to the area of the spinal cord.

This method is “more convenient to the patient and longer-term more commercially attractive,” Dr. Bennett observed.

Gene Veritas (left) with Dr. Bennett at a CHDI conference in February

Dr. Bennett noted that Isis gained valuable experience in drug delivery through a trial of its ASO drug for spinal-muscular atrophy, a childhood neurological disease. Isis also has conducted a Phase I ASO clinical trial for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease.

With the improved delivery method, instead of continuous infusion of the drug, patients will probably need only occasional injections, each one lasting only a few minutes, Dr. Bennett added.

“There’s a long history of safety and efficacy using this method,” he said.

Furthermore, the Isis approach avoids the potentially more risky delivery methods used in two other HD gene-silencing approaches: the use of a virus, or an operation on the skull to introduce the drugs into the brain.

Getting into the brain

To improve the efficacy and safety of the ASOs, Isis and CHDI have been testing them in mice and non-human primates.

One of the key mouse testing sites is Dr. Cleveland’s lab at UCSD, where an HD team led first by Dr. Kordasiewicz and, after her departure to Isis, by Clotilde Lagier-Tourenne, M.D., Ph.D.

In conjunction with experiments in other labs, the Cleveland HD team has demonstrated surprisingly good results.

One major hurdle to treating the brain is the blood-brain barrier, which shields the brain from foreign substances that might cause harm. The barrier makes it difficult to get drugs into the brain.

Significantly, an article recently published in the journal Neuron, with Dr. Kordasiewicz as the lead author, suggested that the ASOs delivered via the CSF reach a wide area of the non-human primate brains, including the regions known as the cortex and the striatum, two areas critically damaged in HD.

As Dr. Cleveland explained, a decade ago scientists viewed neurological diseases as the result of problems in a particular kind of neuron (brain cell). Since then, they have developed a radically different view: the various kinds of cells are linked together in a system – including connections between the cortex and the striatum.

“It’s actually a disease not just of individual neurons but of the whole system, a neuron and the cells surrounding it,” Dr. Cleveland said of HD. “It’s such a simple message. It’s a little surprising that it took so long to realize it. Neurons don’t live by themselves. They require their partners, and the partners develop damage that drives and spreads disease. So, in Huntington’s disease it’s now clear that there’s a partnership between striatal neurons that send projections into the cortex and vice versa.”

Above, Dr. Cleveland in his office at the Ludwig Institute for Cancer Research on the UCSD campus. Below, Dr. Cleveland with lab scientists Jon Artates (middle) and Jihane Boubaker (photos by Gene Veritas).

A ‘Huntington’s holiday’

The most stunning test results involved the amelioration of symptoms.

“Because we are hitting the cortex to such a high level, my prediction would be that we will have a very strong effect on things like cognition and mood and anxiety,” said Dr. Kordasiewicz of the ASOs’ ability to restore brain functions lost in HD. Chorea, the shaking and trembling that occurs in HD, also could be ameliorated, she added.

By reducing the level of mutant huntingtin protein in the mouse brains, the ASOs reversed the HD-like symptoms.

“It was better than we could have imagined. In the sickest animals, we stopped further brain loss,” said Dr. Cleveland “In other mice, a single treatment led to partial reversal of symptoms. And what’s more, the improvements lasted more than six months after a single treatment. And even then, the disease process did not start back up. It was amazing.”

Dr. Cleveland observed that, unlike other kinds of substances the ASOs are made of DNA that isn’t rapidly degraded by enzymes the way many other drugs are affected.

“Once they get intracellular, they’re intracellular acting to catalyze the destruction of the target RNA for, not just hours, not just days, not just weeks, but actually months,” he continued. Just a single injection of the ASO leads to a month of huntingtin RNA suppression in mice. A two-week infusion brings four months of suppression.

The scientists refer to the as yet unexplained symptom-free period after the ASO treatment is gone as a “Huntington’s holiday.”

Dr. Cleveland speculated that “since it takes 30-40 years for HD symptoms to develop. If you could introduce a Huntington’s holiday, maybe you could reset the pathogenic process so that it might take a considerable time to build back up.”

As he and others have observed, success with this approach means people might need to take an ASO HD drug only a few times per year.

As a preventive remedy, a future generation of ASOs might even be prescribed early in life for individuals like me who have tested positive for HD but remain asymptomatic, Dr. Cleveland added.

Watch Drs. Cleveland and Kordasiewicz receive their HDSA-San Diego awards and speak about the promise of their work for an HD treatment in the video below.

HDSA-San Diego 2012 Researchers of Year from Gene Veritas on Vimeo.

Measuring the impact in people

In the final run-up to the proposed clinical trial, the Isis-UCSD-CHDI team and its collaborators are seeking the answer to two more crucial questions: how can the efficacy of the ASO be measured when humans participate in trials? And what is the proper size and frequency of the dose?

The impact of the ASOs on mice and non-human primate brains is fairly easily measured. However, the scenario is different for humans, who cannot be manipulated, sampled, or subjected to the other kinds of experiments done with animal models.

To answer these questions, the scientists are seeking to develop “biomarkers” for the ASO effects.

As Dr. Cleveland explained, the researchers are hoping to find “signatures” in the cerebral spinal fluid of the trial participants that would indicate the impact of the ASO. Those signatures could be related to both to alterations in genes and the secretion of proteins.

“It’s a very big experiment,” Dr. Cleveland said. “We need a partner like CHDI with deep pockets to do this. It’s an expensive experiment, but we absolutely have to do it. Can we find biomarkers? I’m an optimist. We’ll know the answer over the next six months.”

If successful, this experiment will help the scientists determine the amount of drug to give to the patients and provide specific measures of drug impact.

The pharmaceutical firm Novartis has found a way to measure the huntingtin protein in the bloodstream and is seeking to do so in the CSF. The Isis-UCSD-CHDI project also has at its disposal the valuable data from long-term natural history studies of HD patients (TRACK-HD), and it will also probably rely on brain imaging of the trial participants.

Light in the tunnel

In 2013, Isis hopes to select the final ASO drug candidate to move into pre-clinical testing. If that testing is successful, then the company will need another 12-18 months to obtain approval from the Food and Drug Administration to initiate the Phase I human trial.

Planning for Phase I will involve not only the ASO researchers, but toxicologists (who check for safety), pharmacokineticists (who measure the penetration and exit of the drug), and clinicians (who work with and care for the trial participants).

“They’re already starting to engage in the project, because they can see the light at the end of the tunnel,” said Dr. Bennett. “They’re becoming involved in thinking through the strategy of how we’re going to develop this drug.”

Dr. Bennett emphasized that Phase I effort’s main purpose is to measure safety and tolerability – not drug efficacy – although the researchers will also take note of the effects. If Phase I is successful, efficacy comes into play in the potential Phase II and III trials.

“We’re committed to try to do our best to bring that drug forward,” said Dr. Bennett, who noted that the Isis HD team has worked many nights and weekends to speed the project. “There’s still a lot of caveats in there. The best-laid plans sometimes run into roadblocks. But we are very enthusiastic. We’re in this to help patients.”

“For patients and their families, I know it’s too slow, but I don’t think it could be done any faster,” concluded Dr. Cleveland. “I think everyone’s working absolutely flat out.”

Bringing hope to the HD community: Dr. Cleveland at the Gala with advocate Amy Anderson, wife of Craig Anderson, a former pilot afflicted with HD (photo by Gene Veritas) 

Coming down from coming out: recharging the activism batteries

After giving the speech of a lifetime about facing the threat of Huntington’s disease, I need to recharge my batteries.

As readers of this blog know, it's been an intense few weeks. On February 7, I told a meeting of some 250 HD researchers and supporters of the search for a cure that I am gene-positive for the cruel and deadly brain disease that took my mother’s life in 2006.

I had finally gone public after 15 years of hiding my situation. I'd feared genetic discrimination in the workplace and the insurance and healthcare systems.

I still have such fears, but they've diminished somewhat, thanks to the passage of the Genetic Information Nondiscrimination Act in 2008 and the healthcare legislation of 2010, which by 2014 will prohibit denial of coverage to people with pre-existing conditions.

And, because I’m in a race against time as I await an effective treatment, I’ve committed to a bolder stance

Less than a week after my speech, I posted a video of it on this blog. I followed up a week later with an extensive article about the meeting, the “Super Bowl” of HD drug discovery, including videos of my interviews with two leading HD researchers.

In preparing the presentation, I kept thinking of how I was “writing my life.” From mid-December, when I began the speech, until now, I’ve revisited the many memories of my parents and my fears of HD. And I’ve braced myself for the emotional and social impact of leaving the HD closet.

Now I’m taking stock of the whole experience. But it’s not easy to process so many difficult thoughts while handling the many responsibilities of work, family, and community. And there is no “right” or “wrong” way of handling an exit from a closet, especially when in the case of a little-known yet highly stigmatized brain disease like HD. So I don’t yet have any clear conclusions.

In these last few days I did know one thing for sure: I needed to rest up for the next stage of my activism in support of greater public awareness about HD and the need to find treatments and a cure.

Adrenalin mixed with worry

Sharing my story with the scientists who hold my future in their hands left me exhilarated. My keynote speech moved many in the audience to tears.

A number of the scientists later came up to me during the four-day meeting in Palm Springs, California, and said the speech had brought home the reality of HD and inspired them to redouble their efforts.

Later I was interviewed on camera for a forthcoming video about the urgent need for the HD community to participate in clinical and observational trials. Without such help scientists will lack the data they need to develop effective drugs.

I was interviewed by Charles Sabine, a former NBC-TV foreign correspondent and now the international spokesperson for the HD movement. Charles is also HD-positive.

The online video of my keynote speech drew an unusually high number of visits to this blog. People expressed thanks and support.

The speech and my coverage of the meeting brought an adrenaline rush, but also worry about the possible long-term consequences of coming out. I couldn’t point to anything specific, but felt exposed and a bit defenseless. The day after I put the speech online, the emotional overload gave me heartburn.

Translating the science

I had little time to think about the impact of the speech, because I immediately had to shift my focus to comprehending the new research data presented by the scientists. I dedicated each minute of my free time on the weekend of February 19-20 to the update on the meeting.

Although my speech marked a personal milestone, translating the science into language understandable for the HD community presented an equally significant challenge. It is the scientists who will find the solution to HD. The HD movement has become my life’s work, and a big part of that involves informing people of the scientific progress and inspiring them to get involved.

To produce that article I had to get into my special writing zone. It’s a huge challenge to write on HD research, because I was trained in history, not science. The scientists speak in their own highly technical language, and I had to get the translation just right. So I imagined myself somehow fine-tuning my brain for the task.

I relish the challenge, because that kind of stimulus could partially protect my brain against HD’s attack on my mental abilities, including my great passion for writing.

But reporting on the search for treatments also makes me painfully aware of how the disease harms the brain years and even decades before the classic symptoms kick in. It's painful to look at scanning images that illustrate how HD shrinks the brain by causing neurons to die.

In these last few weeks I’ve often felt as if I’m in a daze.The need to deny the reality of HD sometimes makes me feel as if it’s all unreal, as if I’m floating above myself, my predicament, and the scientists and am looking down at it all.

Coming down from coming out

Every beat of the heart requires a rest, so I’ve also spent time more time than usual decompressing.

At one of the dinners for the scientists, the host hotel, the Parker Palm Springs, served a fantastically good wine. Or was it my exhilaration that made the wine taste better? I copied the label information on a napkin: “Hangtime. 2008 Pinot Noir. Arroyo Seco. Force Canyon Vineyard.”

“Hangtime” refers to the period the grapes remain on the vine. It also refers to enjoying the company of good friends and good wine.

I couldn’t find the 2008 vintage of Hangtime in San Diego, but I bought a few bottles of the 2009 vintage to share with my wife and friends.

Each sip reminded me of the speech and the commingling of my hopes with the scientists’ efforts to find a cure. I want so badly for those feelings of hope – and feelings of freedom from HD forever – to hang endlessly in time.

I’m going to track down a bottle of that 2008 vintage and keep it as a remembrance of the meeting. I’ll uncork it the day the scientists have found an effective treatment that saves everybody in the HD community from its devastating symptoms.

Keeping a balanced life

As many readers of this blog may have concluded, I’m a workaholic. That keeps me focused. But sometimes I let my activism consume me. Then I must remind myself that, no matter the circumstances, life requires balance.

A few weeks ago our “miracle baby,” who was born HD-negative in 2000 after we had her tested in the womb, lamented the fact that I had not taught her how to throw a ball properly.

After work one afternoon, I stopped at Target to choose a cushy ball the size of a softball. I took my daughter to the park, and we practiced tossing it back and forth. When it was time to go, I made her throw it to me and catch it three consecutive times without a miss before we could leave.

In the days that followed, thinking of the ball became the antidote to my workaholism.

It’s also a reminder that my daughter needs me.

Keeping the balance is a huge challenge, because for me to be with my family in the long run, I must spend time away from them in the short run working for the cause. However, although scientists are increasingly optimistic about a treatment, nobody can predict exactly how or when they will find one.

Looking ahead

So now it’s time to recharge my mental, emotional, and physical batteries for the next wave of activism. The keynote speech is already creating new opportunities for me to contribute to the cause.

Tomorrow evening, February 28, I will speak to the local HD support group on my coping strategies.

In early May I will make a similar presentation to the annual convention of the Northern California chapter of the Huntington’s Disease Society of America.

I’m also planning a trip to Cambridge, Massachusetts, to visit the headquarters of Alnylam Pharmaceuticals, which is getting ready to apply for permission from the federal government to conduct human trials for its potentially revolutionary remedy, an RNA interference drug, to stop HD at its genetic roots. I will write about Alnylam in future articles.

As I step up my public advocacy, I’m embarking on a new phase in my life. More than ever, I’m going to need large quantities of positive energy.