Quickening the pace towards a Huntington’s disease gene-silencing clinical trial: pharma giant Roche, Isis enter partnership

With an infusion of $30 million and access to new technology from the Swiss pharmaceutical giant Roche, Carlsbad, CA-based Isis Pharmaceuticals, Inc., hopes to shorten the timetable for a clinical trial of a potential breakthrough drug for Huntington’s disease. It would attack the disease at its genetic roots and could serve as a preventive medicine.

The partnership, announced April 8, puts Isis in a position “to move very aggressively to getting the drug into clinical trials,” Frank Bennett, Ph.D., the Isis senior vice president for research, said in a phone interview. “It should accelerate the program.”

The deal, which could bring Isis up to $362 million in payments for developing and licensing the drug plus royalties on sales should it prove successful, provides a key piece of the puzzle for the company’s HD program. As a dynamic mid-sized company focused on drug discovery but lacking the capital and infrastructure for large-scale clinical trials and drug commercialization, Isis has finally secured the partner necessary for bringing the potential HD drug to market.

“This is the best news,” said Don Cleveland, Ph.D., an Isis collaborator who helped envision the treatment of HD with the company’s gene-silencing antisense oligonucleotides (ASOs). “Running a clinical trial takes substantial dollars. Isis is a smaller company. Roche is one of the world’s largest and most successful pharmaceutical companies.”

The partnership gives Isis the “confidence” necessary to move from the early to later stages of the clinical trials, Dr. Bennett said. Roche, with its long experience in central nervous system drugs such as Valium, in use since the early 1960s, will not be “dropping the ball as a partner,” he added.

Dr. Frank Bennett (photo by Dr. Ed Wild)

                                                                                                                       

In line with earlier projections, Dr. Bennett stated that Isis still hopes to begin the clinical trial during the first half of 2014.

Shuttling drugs into the brain

The ASOs diminish the production of the huntingtin protein by eliminating huntingtin RNA in brain cells, which are destroyed in HD, producing motor, cognitive, and psychiatric difficulties in affected individuals. (Click here to read more about the efforts to design the drug and bring it to trial.)

Isis and Roche will experiment with the latter’s “brain shuttle” technology, which, if successful, would allow greater penetration of the drug into the brain and make it far easier for patients to take.

Isis first aimed to implant a pump in a patient’s abdomen and inject the drug directly into the brain. Then it moved to an injection into the cerebral spinal fluid (CSF) through a quarter-sized port implanted near the rib cage, with a catheter running to the area of the spinal cord.

However, as Dr. Bennett explained, with the brain shuttle technique, patients would simply need a subcutaneous injection (under the skin) similar to the kind taken by diabetes patients.

The brain shuttle would “allow us to use systemic dosing,” Dr. Bennett explained. (Systemic dosing means the drug enters the bloodstream and is thus more available in the body in comparison with an injection into the CSF.)

“It’s much more convenient,” he added. “It’s a better tolerated therapy. It could capture the symptoms earlier, maybe even prevent the development of the disease.”

Glimpsing the Holy Grail?

That convenience also makes it easier to administer the drug to gene-positive asymptomatic individuals, Dr. Bennett noted.

For ethical and scientific reasons, people in this group (including me) have rarely, if ever, participated in HD clinical trials. Basically, scientists haven’t yet figured out how to measure how a drug could benefit this group. In addition, its risk-benefit ratio is higher than it is for people with symptoms. Solving these problems, and thus completely preventing HD (as well as other neurological diseases such as Alzheimer’s), is what I have called the Holy Grail of the research community.

For the first time, the Isis-Roche partnership suggests how the grail might be found. With reduced risks, participation in trials becomes more attractive, and ethical barriers diminish. In addition, the very entry of asymptomatic people into a trial permits the collection of data about efficacy specific to that group.

However, Dr. Bennett cautioned that this approach would most likely be reserved for second-generation clinical trials. Until the initial trials are completed, it’s impossible to venture a guess about the timetable for a second generation.

“As a scientist, you can always make something better, but you have to be careful,” he said of the time needed to develop the brain shuttle for ASOs. “For a patient that’s suffering from the disease, you don’t want to over-engineer and delay getting it to the patient.”

Dr. Cleveland pointed out that the brain shuttle approach is new and has yet to be proven as a way to transport drugs into the brain.

“That’s precisely why you want to have partners like Roche,” he said. “They’ve been delivering things to the central nervous system for a long time. There’s tremendous promise. The challenge will be to bring that promise into real fruition.”

Isis and Roche will conduct joint research to discover whether they can attach the ASO to molecules that naturally shuttle other, necessary molecules into the brain across the blood brain barrier, which shields the brain from foreign substances that might cause harm and prevents the ASOs on their own from entering.

Key details and collaborators

“Huntington’s is a severely debilitating neurodegenerative disease and a large unmet medical need,” Luca Santarelli, Head of Neuroscience and Small Molecules Research at Roche, stated in the press release announcing the partnership. “Treatments are urgently needed, and we believe that the Isis approach in combination with Roche’s brain shuttle represents one of the most advanced programs targeting the cause of HD with the aim of slowing down or halting the progression of this disease.”

Under the deal, the $30 million investment from Roche will underwrite the project through Phase IIA of the three phases of the first-round clinical trial, with Isis retaining control of the project, Dr. Bennett said. If Phase IIA proves successful, Roche would conduct the more extensive Phase III trial, seek regulatory approval for the drug, and market it.

The agreement also stipulates that over time Isis will reimburse the CHDI Foundation, Inc., the multi-million-dollar non-profit virtual biotech firm that funded and advised the HD research at both Isis and Dr. Cleveland’s lab at the Ludwig Institute for Cancer Research at the University of California, San Diego. CHDI will initially receive $1.5 million, with additional reimbursements occurring as Isis receives project milestone payments from Roche. CHDI will continue to advise Isis and Roche on HD research.

“This is an exciting development for the HD community, and a testament to the excellent work that Isis has done to develop their oligonucleotide therapeutic for HD,” said Robi Blumenstein, the president of CHDI Management, Inc., the firm that carries out the goals of the CHDI Foundation. “It's very encouraging that Roche, a pharmaceutical company with a great track record in central nervous system disorders, has now entered into developing treatments for HD. CHDI looks forward to working with both companies to steer this novel approach to the clinic as soon as possible."

Isis, Dr. Cleveland, and CHDI are currently conducting a large experiment to find HD biomarkers (signs of disease) that will enable them to determine the proper dose of the ASO drug and to measure its impact during the clinical trial.

David Corey, Ph.D., of the University of Texas Southwestern also collaborated with Isis on the gene-silencing project.

(Next time: my personal thoughts on the Isis-Roche project as a powerful new sign of hope for the HD community.)

Brazil’s big place on the Huntington’s disease map

The defeat of Huntington’s disease could hinge in good part on how well the HD movement in developing countries, in cooperation with national governments and international HD organizations, can alleviate poverty and other social problems that hinder efforts to engage affected people in the fight against the disease.

Eyeing the excellent scientific progress towards treatments but also the barriers to greater family involvement, the global HD community this year will focus on Brazil, a leader in the developing world and the host of this year’s World Congress on Huntington’s Disease, scheduled for September 15-18 at the Sheraton Rio Hotel & Resort in Rio de Janeiro.

The sixth world congress since the inception of the event in Toronto in 2003, this first-ever gathering of this magnitude in Latin America will draw hundreds of HD researchers, physicians, activists, and affected individuals and families from around the region and the world to hear presentations on the latest HD research and participate in activities aimed at helping HD people and their families cope with the disease.

Brazil, the host of the 2014 World Cup in soccer and the 2016 Olympic Summer Games,  has emerged as a global economic power, tied at sixth with the United Kingdom in world Gross Domestic Product rankings.

With over 190 million people, the world’s fifth largest population, Brazil could add potentially hundreds, if not thousands, of participants to the recently inaugurated Enroll-HD program, an international study of HD patients, at-risk individuals, and their families. Enroll-HD aims to increase knowledge of the disease and the pool of participants for research studies and clinical trials, which are crucial for developing and testing treatments.

However, despite its growing geopolitical and scientific-medical significance, Brazil remains far from First World status, with tens of millions of people still living in poverty unimaginable to most Americans and Europeans, high levels of corruption, frightening urban violence, and a weak public primary and secondary educational system.

On the HD front, awareness, fundraising, and research in Brazil lag far behind the U.S., Canada, and Europe.

“The congress had to be in Brazil,” said Dr. Mônica Santoro Haddad, a leading neurologist and member of the local organizing committee. “Brazil needs to take on a position of leadership in the region.”

However, Dr. Haddad added that within Brazil the HD community must be “more active in its decision-making, not passive.”

A herculean task: changing culture

A native of São Paulo, South America’s largest city, the 48-year-old Dr. Haddad is the director of the Brazilian Academy of Neurology and an active member of the American Academy of Neurology (AAN).  In 1997, she helped start the São Paulo-based Associação Brasil Huntington (ABH), where she serves as medical advisor.

In her 25-year career, Dr. Haddad has attended to some 400 HD-affected families at her clinic in the region’s largest hospital, the Hospital das Clínicas of the University of São Paulo. She has followed 50 more families in her private practice.

At the 65^th AAN meeting in San Diego last month, the ebullient Dr. Haddad granted an interview about HD in Brazil and the goals of the World Congress. She spoke passionately in Portuguese – the language I learned for my academic research as a historian – about the great hopes for HD treatments in the coming years, the need for the Brazilian HD community to become better organized, and Brazil’s potential to make a difference in the HD field.

Dr. Mônica Santoro Haddad (photo by Gene Veritas)

“We’ve got a herculean task before us, which is to change two cultural trends,” Dr. Haddad said. “One is the question of discrimination. Within the families themselves I hear, ‘Whoever has the disease is a worse person than those who don’t have it.’

“That makes absolutely no sense. People who have Huntington’s are more than a defect in their genetic material.”

The other trend involves resistance to private fundraising, a societal challenge throughout Brazil. Whereas private U.S. sources have provided hundreds of millions of dollars for research and care programs over the past two decades, the ABH gets by on a startlingly humble annual budget of $40,000, all of it from small donations from HD families.

“A cultural trait of Brazilians that is very different from Americans is that many Brazilians don’t have the habit of donating money or time to causes, whether they be scientific or cultural or artistic,” said Dr. Haddad. “I admire that in American culture.”

“Unfortunately, I’ve seen people in my private practice who have a lot of money and use that money to simply hide or minimize the fact that they’re from families with Huntington’s,” she added. “In Brazil, people don’t donate, because they believe that if they do, they’ll be compromising themselves and publicly assuming a cause. They’re not capable of donating anything to the cause, even anonymously.”

The Brazilian way of denial

As in the U.S. and elsewhere, fear and denial frequently underlie people’s decisions to avoid genetic testing and facing the terrible medical and social challenges posed by the disease.

Many Brazilians retain “prejudice against disease,” Dr. Haddad lamented.

“Brazil is a country where, ten years ago, and even among people today, almost nobody said the word ‘cancer,’” she said. “People said: that disease. That prejudice is something that people inherited. They want to keep a distance between themselves and disease, because it’s a magic way of protecting themselves against disease. Embracing a cause of that type and assuming publicly that there’s a problem is very difficult.”

With HD, she added, people rely on a similar “magical way of thinking, such that, if one doesn’t undergo genetic testing, it’s as if one doesn’t have the disease. ‘If I don’t think about it, it ceases to exist.’”

Similar patterns of denial hamper awareness-building and advocacy, Dr. Haddad continued.

“My impression is that Brazilians think that if they don’t know much about the disease, or if they don’t participate in some way and attend meetings, that they will perhaps be protected,” she said. “Precisely, the challenge for people at risk for the disease is to understand that they need to participate in clinical studies, the ABH, and epidemiological studies. Without their help, we’re not going to find the best solutions for Huntington’s patients.”

The situation described by Dr. Haddad is exacerbated by the general ignorance about HD in Brazil. Most physicians and other health professionals fail to understand the symptoms, she said.

“Unfortunately, there must be a lot of people incorrectly diagnosed, simply diagnosed as having ‘degenerative disease X,’ without anybody following up,” she said. “Perhaps the government doesn’t even know exactly what Huntington’s disease is, because it has to deal with so many other widespread and serious health problems that affect our population.”

From handouts to changing lives

Advocacy faces further hurdles in the way Brazilians relate to government, Dr. Haddad observed. In Brazil, many people “wish for handouts.”

“Unfortunately, some people are so poor, that they want to ask for diapers or a simple dwelling to reside in,” she explained. “I believe that the function of the ABH is to obtain benefits for the entire community. It’s okay if you need a pack of diapers. But that is not going to change people’s lives.”

Among other goals, Dr. Haddad explained, the ABH and the HD community need to lobby the Brazilian Congress, push for a national HD day or month, continue to raise awareness about the disease among health professionals, obtain social security benefits and free medications for HD-affected individuals, and seek funding from government agencies.

Although São Paulo has world-class physicians and medical facilities, she runs her HD clinic with just two other health professionals and an occasional intern.

“It’s important to train health professionals capable of detecting Huntington’s disease or at least suspecting what it is and then referring the person to a larger facility to make the diagnosis,” Dr. Haddad explained. “We need to create ways, in a country the size of Brazil, to transfer this knowledge via video-conferences or a distance-learning center that can answer people’s questions.”

Individual members of the HD community also need to understand the impact of their inaction, Dr. Haddad added.

To illustrate her point, she used the example of organ donations. Many people reject the idea without thinking of the consequences, she said.

“I joke with them: ‘If you wrote down that you don’t want to receive an organ donation, that would require you to think more about the matter and to put yourself in someone else’s shoes,’” she said.

Goals at the World Congress

Together with other physicians and leaders of the HD community, Dr. Haddad hopes to use the 2013 World Congress to stimulate the movement in Brazil.

“The families are excited,” she said.

Dr. Haddad observed that the congress will provide them with access to world-class expertise on HD. The official language will be English, but all sessions will have simultaneous translation into both Spanish and Portuguese.

Dr. Haddad also hopes that, by exposing Brazilians to people from HD entities in other countries, the congress will drive home the point about “the importance of organized participation.”

The congress also has created an opportunity for the ABH and neurologists to inform Brazil’s Ministry of Health about HD, invite ministry officials to participate in the congress, plan strategies for improving the lives of HD-affected families, and pave the way for the success of Enroll-HD.

Yet another key goal will be to put “Brazil on the map of Huntington’s disease research,” Dr. Haddad added. In this respect, the congress will demonstrate to foreign researchers the excellence of Latin American researchers, she said. It’s also an opportunity to recall the key role of HD people in Venezuela in the discovery of the HD gene, a process that culminated in 1993. (At 2 p.m. EDT tomorrow, April 3, a symposium on the 20th anniversary of the discovery will take place in Washington, D.C. It can be viewed live at: http://www.ustream.tv/channel/hdgene.)

In presenting the aims of Enroll-HD at the congress, Dr. Haddad and a colleague hope to suggest to Latin America’s basic researchers the opportunities for research in the HD field. Currently, only a few basic researchers in Brazil focus on HD.

She said that they want to show Brazilian scientists that HD “is a very interesting disease to study,” providing, for example, a model of experimentation that can be used in other areas of research.

Brazil’s contribution to Enroll-HD

For the first time, Enroll-HD is taking the study of HD and the search for treatments global in a coordinated way. Working with groups such as the Latin American Huntington’s Network, it seeks to secure the international cooperation and volunteers necessary for success.

                                                  

Supported by the CHDI Foundation, Inc., the multi-million-dollar non-profit virtual biotech firm aimed solely at finding HD treatments, Enroll-HD in Latin America gets under way this month in Argentina. Dr. Haddad, the lead coordinator of the project in Brazil, estimated that it will start there in the first half of 2014.

Although no study exists documenting the number of HD-affected people in Brazil, Dr. Haddad believes that, as in the U.S., about one in 10,000 people have the disease. Thus, as many as 19,000 people in Brazil suffer from HD. Because the country still has many large families, the number of people at risk is many times that number, she said.

As in some other Latin American nations, where patterns of colonization and intermarriage in some isolated areas led to a prevalence of HD at rates hundreds of times higher than the U.S. average, Brazil has some examples of an extremely high occurrence of the disease. In the town of Feira Grande, for example, researchers found 22 patients in a population of just 22,000 people – ten times the U.S. rate.

“Brazil can contribute a lot (to Enroll-HD), because we have a large number of people who could participate in clinical trials and who might be those ‘gifts of nature,’” Dr. Haddad stated. “These are people who have developed the disease in a different, less harmful way, due to a modifier gene, for example, and who can be studied so that we can reproduce their experience for others through the use of new kinds of treatments.”

Enroll-HD will include the collection of blood, cerebral spinal fluid, and potentially other biological samples (such as skin and urine) to be shipped to a bio-repository in Milan, Italy. Researchers everywhere will be allowed to apply for permission to use the samples.

Extending the work she and others have carried out in Brazil and other parts of Latin America in recent decades, Enroll-HD will enable physicians to improve the care of HD patients, especially those living in poverty, Dr. Haddad concluded.

As part of the worldwide effort against HD, those patients could help provide the keys to victory.

(For a recent article on the question of poverty and HD research in Latin America, click here. Also see the ongoing story of efforts by the Hereditary Disease Foundation to assist HD families in Venezuela by clicking here. In a future article I will feature the work of the Associação Brasil Huntington.)

Big decisions while facing the threat of Huntington’s disease

At every turn of life, we all make big decisions such as choosing a career, a mate, a home, and the number of children to conceive.

Living with the knowledge of a positive test for a devastating condition such as Huntington’s disease radically complicates such decisions. Coupled with the deep stigma associated with HD, the fear of the onset of symptoms magnifies the stress and doubt that come with such turning points.

As I have frequently revealed in my writings and in speeches about HD, I have faced life-changing decisions about a feeding tube for my HD-stricken mother, my genetic test, and the test of our daughter while still in the womb. (Thankfully, she tested negative!)

Planning for the inevitable symptoms of this currently untreatable disease has also profoundly altered my career, leading me into a new field far different from my original focus on Brazilian history: the history of science, technology, and medicine.

With my definitive exit from the “HD closet” last fall, I have begun to integrate this new intellectual passion into my professional life.

Professional excitement

Lately, however, I’ve relived the intensity of how the threat of HD affected my professional decisions.

With the surprise resignation of Pope Benedict XVI on February 11 and the emergence of several potential successors from among Latin America’s cardinals, my expertise on the Roman Catholic Church’s actions in the region and its relations with the region’s dictatorships – topics usually of no interest to the media and the general public – suddenly were in demand.

The election of Pope Francis I created great excitement: his initial attitudes and actions indicated that he might very well attempt to clean up the corruption and abuses that have plagued the institution.

At the same time, it rapidly became apparent that the new pope had had his own complex and (to some) controversial relationship with the Argentine dictatorship, which carried out a “dirty war” against Argentines from 1976-1983.

In the period before and after the election of Pope Francis I, I gave eleven interviews and answered a number of other queries from newsmagazines and radio and TV outlets.

My personal excitement culminated with the publication on March 17 of an op-ed article, outlining the potential paths of the Church under Francis I, in one of Brazil’s most prestigious newspapers, the Folha de S. Paulo, followed  by a quotation from me about the Argentine branch of the Church in a front-page story in The New York Times.

As I told a number of friends, never before and probably never again will my scholarly work on the Catholic Church command so much attention in the United States.

Throughout all this, I began to relive the past thrills and satisfaction of researching the Church, publishing books on the topic, and discussing my work in the Brazilian media.

My wife seemed especially happy to see me enjoying, for the first time in a very long while, recognition for my original career path. For her, it was a relief from that dogged, sometimes seemingly one-dimensional aspect of my life involving the fight against HD.

Second-guessing the past, but welcoming the future

As a result, I began second-guessing my decision in 2007 to turn down a job to help run a prestigious Latin American studies center in Florida in order to remain in biotech-rich San Diego to focus on the fight against HD. Staying put also helped safeguard my family’s financial future by allowing my wife to keep her good job and better-than-average retirement plan – absolutely essential if HD were to leave me disabled.

I thought of the HD people I had recently read about who had roughly the same degree of genetic mutation as I did and managed to avoid symptoms until their sixties and even continued to work after onset.

However, in the process of second-guessing, I recalled how I made that decision when the memories of my mother’s demise just a year and a half before still haunted me.

In hindsight, it’s easy to argue that I should have taken the other job and not worried so much about HD.

However, hindsight also reminds me of how HD completely destroyed my mother’s ability to work, to communicate, and to care for herself.

My wife and I made our big decision with the best information available to us at that moment.

I quickly reminded myself that rather than reliving the past, I must look to the future, value the intellectual flexibility of my university, and fulfill the plans I have mapped out for myself. I will be seeking connections with my university’s neuroscience program and social outreach project in order to promote brain health as a national priority.

Indeed, my dean has fully supported me after my exit from the HD closet. I felt especially reaffirmed with the publication of a feature article about my journey with HD on the university’s website.

The decision to pursue the history of science, technology, and medicine has exposed me to new vistas of the human story. HD is a challenge – but also a gift that has led to profound intellectual and personal growth.

The real successes and challenges

I savored my public moment as a Latin America scholar.

However, it stood in sharp contrast to the intensity and immensity of the challenge to avoid HD symptoms and contribute to the defeat of the disease.

While friends and colleagues were impressed with the recognition of my expertise, I quietly pondered the truly significant accomplishment for me during the week of Francis I’s election: the successful arrangement of a meeting between Paulo Vannuchi, Brazil’s former Minister of Human Rights, and Taíse Cadore, the president of the Associação Brasil Huntington. They discussed the crucial need to involve Brazil’s Ministry of Health in the fight against HD in Brazil, which will host the 2013 World Congress on Huntington’s Disease from September 15-18.

Ultimately, scientists’ work will go for naught unless events such as the World Congress can draw more people into the HD cause and involve them in the all-crucial research studies and clinical trials.

Participating in a study

On March 13, as I monitored the Internet for news of the papal conclave, I spoke to a researcher at the Huntington’s Disease Society of America Center for Excellence at Iowa Hospitals and Clinics, one of the sites for a key study known as PREDICT-HD, an observational study of the earliest signs of HD that needs asymptomatic, gene-positive volunteers.

PREDICT-HD will help establish ways to measure the efficacy of potential treatments.

Participating in PREDICT-HD represents another big decision for my family and me. The study requires the presence of a spouse or partner, who must answer a questionnaire about the gene-positive individual. All three of us must spend two days traveling and at least two days in Iowa.

The PREDICT-HD also involves a voluntary spinal tap so that cerebral spinal fluid from gene-positive people can be studied for the effects of HD and ways to measure the efficacy of potential treatments.

Spinal taps are routine but, like any procedure, involve risks such as a debilitating headache that could require emergency room treatment. In my case, it means that I will probably notify my health insurance plan for the very first time of my gene-positive status. I want to make sure I can safely undergo the tap, and I want to have my plan doctors on standby in the event of complications.

In and of itself, informing my health plan about HD represents yet another significant shift in my medical, psychological, and emotional approach to the disease.

Channeling the positive energy

As the HD researcher and I finished our discussion about PREDICT-HD, I saw the announcement of breaking news about white smoke from the Sistine Chapel: a new pope had been chosen.

Minutes later, my daughter and I watched as Francis I appeared on the balcony of St. Peter’s Basilica in Rome and humbly prayed the Our Father and Hail Mary with the crowd gathered below – the same prayers she and I say together each night, alternating in English and Portuguese, before she goes to sleep.

I felt a new beginning for the Church.

In the days since then, I have frequently asked myself how I can channel the deep fulfillment and positive energy from my study of this troubled but nevertheless key institution into the effort to relieve the suffering caused by Huntington’s and so many other devastating diseases.

As I wrote in my op-ed piece on the pope, Francis I “seems to be saying that believers, and the rest of the world, must rediscover the fundamentals of human existence.”

In his inauguration homily on March 19, Francis I stated that “authentic power is service.” As pope he must protect “the hungry, the thirsty, the stranger, the naked, the sick and those in prison.”

For me, this means protecting my family from the consequences of HD and striving to do my small part to help others.

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.