Tuesday, March 20, 2012

A new, more holistic view of Huntington’s disease: the systems/P4 approach

When I learned in late 1995 that my mother suffered from Huntington’s disease, a disorder unknown to my family, my reaction went from perplexity to utter shock as I listened to the details: HD caused shaking and severe dementia, was fatal, and had no treatment or cure.

Over the next decade, as my mother lost the ability to walk, talk, eat, and care for herself, her doctors could do little to help.

With a 50-50 chance of inheriting HD, I felt desperate as I waited in limbo. In 1999, my positive test for HD multiplied my fears.

When my mother died in 2006, a treatment didn’t even appear remote.

Even today, the medicines prescribed for HD patients treat only symptoms, sometimes with serious side effects. They do not arrest the disease in any way.

The lack of therapies (a medically more appropriate word than “treatments”) devastates affected families, perhaps more than any other of the cruel realities of HD.

However, as I described in my previous two articles, leading HD researchers are planning for eight new clinical trials in just the next two years (click here and here to read more).

The vastly increased knowledge of HD’s causes and the very real possibility of effective therapies behoove us to think about HD in a radically new way. Instead of reacting with the traditional (and quite understandable) fear and pessimism, I believe we must now embrace hope and optimism.

Rather than anticipating the worst, we must expect the best, even if we cannot predict the timetable.

Shifting from ‘incurable’ to ‘treatable’

To turn the emotional tide and spur greater patient and family involvement in crucial research and clinical trials, the HD community must replace the phrase “HD is incurable” with “HD is treatable” or, perhaps more precisely, “HD will be effectively treatable.”

“For so long we’ve talked about HD as an incurable disease,” I told an audience of some 100 people at the southern California Huntington’s Disease Regional Education Day at the University of California, Irvine, on March 10, sponsored by the Huntington's Disease Society of America (HDSA), Lundbeck, and Remind. “That keeps people behind the mask, keeps them in the closet, keeps them in denial. But the fact that you have the trials coming on line means that this statement is no longer accurate. It’s no longer an incurable disease. I believe it’s a disease that’s going to be treated, and going to be treated successfully sometime in the next five to ten years.

“So going back to the old HDSA phrase of some years ago: let’s make this the last generation with HD. I believe it’s going to be the last generation with HD, or that has HD in the way we’ve known HD, because I think we’re going to be controlling and managing HD.”

You can see the entirety of my speech in the video below.

Solid reasons for hope

People have occasionally cautioned me against raising false hopes, warning that if a potential drug fails, some in the HD community might withdraw from involvement in research and clinical trials. Many remember how in the early 2000s some people placed great hope in LAX-101 (also known as Miraxion or ethyl-EPA), a fish-oil extract, only to experience a letdown after mainly ineffective clinical trial results.

The cold, hard fact is that 90 percent of all clinical trials do not produce an actual drug. It takes time for scientists and drug companies to develop, test, and fine-tune drugs.

Furthermore, scientists do not view those 90 percent as unsuccessful or “failures.” Rather, a trial that ends without a successful therapy simply indicates that researchers should make a correction in the path or choose a different one.

Therefore, we must not give up if a trial or therapy does not fulfill our personal expectations. Drug discovery requires the participation of the entire HD community. Only by working together can we assemble all of the pieces of the therapy puzzle.

I also think that we have solid reasons for hope.

Having followed HD research the past 15 years, I believe the current lineup of planned trials stands out as qualitatively far different from LAX-101 and other supplement-like substances in other trials or drugs originally designed for other conditions that didn’t prove effective in HD.

The new generation of potential drugs benefits from new biological discoveries (such as RNA interference), new drug-discovery technologies (such as high-throughput screening), and a much greater (though still far from complete) understanding of how HD damages the brain.

In addition, in the words of Dr. Robert Pacifici, the chief scientific officer of CHDI Management, Inc., the multi-million-dollar HD therapy initiative, the new HD drug candidates are “custom-crafted” for HD.

A visionary turns to HD research

The annual CHDI HD Therapeutics Conferences provide a panorama of the progress in HD research. I am preparing a report on the scientific findings of the seventh conference, held February 27-March 1 in Palm Springs, CA.

Here I want to reflect on one speaker, Dr. Lee Hood, whose scientific vision is beginning to influence the search for HD therapies.

An M.D., Ph.D., Dr. Hood worked with colleagues to invent four instruments important for the success of the Genome Project (as well as other research): the DNA sequencer and synthesizer and the protein sequencer and synthesizer. Dr. Hood helped to found 14 biotech companies, holds 30 patents, and stands among only ten people in the world to belong to all of three major American scientific organizations, the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. In 1987 he won the Lasker Basic Medical Research Award (the American equivalent of the Nobel Prize).

In 2000, Dr. Hood founded the Institute for Systems Biology (ISB). Located in Seattle, the non-profit ISB teams scientists and technologists from many disciplines to pioneer the future of research in biology, biotechnology, medicine, environmental science, and science education. Dr. Hood is the ISB president.

Dr. Lee Hood at the 7th Annual CHDI HD Therapeutics Conference (photo by Gene Veritas)

When he turned 70 in 2008, Dr. Hood stated that he aimed to achieve the “most ambitious things … in my career,” including the advancement of systems biology and advocating for the widespread adoption of “proactive P4 medicine” (predictive, preventive, personalized, and participatory).

Among other cutting-edge collaborative projects, ISB has pioneered proteomics, the study of the more than 23,000 proteins in the human body.

“What we’ve done is to democratize proteins – that is, make them accessible to all biologists – just as the Human Genome Project democratized genes and made them available to all biologists,” Dr. Hood told the audience at the HD Therapeutics Conference.

A new, even more exciting project aims to develop “global proteomic analysis” by digitizing all of the human peptides (the chemical building blocks of proteins), Dr. Hood added. Just as people can hone in on a geographic location using Google Earth, scientists will soon compare peptides in a digital catalogue, he said.

The next stage will involve studying proteomics and genomics together, he said.

The importance of systems biology

In his HD Therapeutics Conference presentation, “Systems Approaches to Neurodegenerative Diseases and the Emergence of Transforming Technologies,” Dr. Hood explained systems biology (SB) and how it can impact the search for HD therapies.

SB emerged because of two revolutions: Darwin’s work on evolution, which revealed the enormous complexity of biology and disease, and the late-20th-century explosion in digitized biological information.

“We need this thing called systems biology to de-convolute that complexity,” Dr. Hood stated.

In a nutshell, SB offers a holistic view of disease. In Dr. Hood’s words, the body is a hierarchical “network of networks” that interact – beginning with genes, extending to molecules, reaching the organs, rising up to the individual human, and ultimately including society and the physical environment.

In my own shorthand, I think of SB as the “big picture of disease.”

SB uses the power of computing to mine, integrate, and visualize very large and complex sets of biological information, Dr. Hood added.

He described the SB approach to disease as providing an “informational view of science” that seeks to “capture the dynamics of disease.”

In this approach, biology drives technology, which in turn drives analytical tools (computation).

“It’s this holy trinity of biology driving technology driving computation that’s really at the heart of systems biology,” Dr. Hood explained. “I realized this first in the context of developing the automated DNA sequencer.”

SB scientists seek to tackle a complex system like HD, build a model of the disease, test that model, and then “perturb” its system repeatedly to see the disease mechanism at work. From this experimentation, they draw conclusions about the disease and how to treat it.

Hunting for HD modifier genes

In collaboration with leading HD specialists, ISB has set out to identify modifier genes for HD. HD results from a mutated form of the huntingtin gene, but one or more modifier genes may affect the onset of the disease. This would help explain why onset occurs at different times in people with the exact same degree of mutation.

To conduct this research, ISB has resorted to the SB approach of gathering large amounts of genetic information.

“We’ve now analyzed more than 60 human genomes from families that have Huntington’s disease,” Dr. Hood told the HD Therapeutics Conference audience. “What we’ve found is these families place enormously interesting constraints on areas where you may find modifiers, but we don’t have sufficient data at this point to really identify candidates. What we’re excited about is integrating these data together with the GWAS (genome-wide association study) data that will be coming later in the year.”

SB and a better understanding of HD

Dr. Hood concluded that SB can assist a search for HD therapies in four other ways. First, it can bring “new insights” into how HD works.

Secondly, “we can make blood into a window for health and disease” by discovering and measuring markers of “drug toxicity as well as disease diagnostics.”

Third, in line with its holistic outlook, SB provides “new approaches to analyzing multi-organ responses.” So far, most HD research has focused on the brain. However, scientists know that the huntingtin gene is expressed in every cell in the body and affects muscle and fat.

Fourth, SB presents “new approaches to drug target discovery” that could speed the arrival of therapies.

Finally, Dr. Hood added, “the digitization of information is going to be absolutely fascinating,” allowing scientists ever greater access to what happens in HD patients and helping them to plan treatments.

You can watch the entirety of Dr. Hood’s presentation in the video below.

P4: predictive, preventive, personalized, participatory

SB is laying the basis for P4 medicine, which holds great relevance not just for HD, but all diseases and the promotion of wellness in a future global system of health.

“P4 medicine, the clinical face of systems medicine, has two major objectives: to quantize wellness and to demystify disease,” Dr. Hood and a co-author write in an article in the March 2012 issue of the journal New Biotechnology that he sent me shortly after the HD Therapeutics Conference. “Patients and consumers will be a major driver in the realization of P4 medicine through their participation in medically oriented social networks directed at improving their own healthcare.”

Several organizations have partnered with ISB to pioneer programs in P4. If it is implemented on a wide scale, Dr. Hood predicts that it will revolutionize our healthcare system. Costs will plummet, everybody will carry a health monitoring device, and diseases will be predicted and prevented long before onset as the result of tiny blood samples taken from a pin prick, the article states.

“P4 medicine will not be confined to clinics and hospitals,” the article continues. “It will be practiced in the home, as activated and networked consumers use new information, tools and resources such as wellness and navigation coaches and digital health information devices and systems to better manage their health.”

Care will be “tailored to the circumstances of each individual.”

An amazing transition

Systems biology and P4 medicine provide a vastly different picture of Huntington’s disease from the largely hopeless one painted for me and my family after my mother’s diagnosis in 1995.

And we felt so alone in the impersonal world of traditional medicine.

The fresh, fundamental SB/P4 approach has led to a deeper understanding of the work that lies ahead in the search for HD therapies.

CHDI has adopted the SB approach by hiring one of its key practitioners, Dr. Keith Elliston, to serve as its vice president of systems biology. Dr. Elliston also spoke at the HD Therapeutics Conference.

Dr. Keith Elliston (in cap) confers with scientists at the HD Therapeutics Conference (photo by Gene Veritas).

“I’m also very excited that CHDI has chosen to embrace systems biology and to make that a key tenet of its drug-discovery process,” Dr. Nathan Goodman, an ISB researcher and member of an HD-affected family, told the audience. “In essence, this makes CHDI the first systems-biology-driven therapeutics company, yet another in the long line of firsts that CHDI has accomplished. This is a very big step not just for the Huntington’s disease field, but for all of biology, all of life sciences, the entire industry of therapeutics. This is an amazing transition by CHDI.”

As SB and P4 could very likely represent the future of medicine, I’m betting they will also play a major role in removing HD as a threat to me, my family, and the tens of thousands of families around the world impacted by HD.

We in the HD community have fulfilled the first P: genetic testing allows us to predict our future.

We now must focus on the other Ps: preventing HD; receiving personalized diagnosis and treatment that will optimize our health; and attaining wellness and a long life as a result of having helped find effective treatments through proactive participation in HD research and clinical trials and the contribution of our biological information to a global data bank.

Wednesday, March 07, 2012

The first dose is hope: moving towards treatments for Huntington’s disease

With its incurable genetic attack on the brain, Huntington’s disease wreaks havoc on its victims and their families, leaving them helpless, bereft of hope. I felt powerless as I watched my own HD-stricken mother become a mere shadow of herself and then worried about my own onset after testing positive for HD in 1999.

However, we have reason for hope. After many years of quiet but steady progress, drug makers are beginning to harvest significant results in the quest for treatments.

Since my mother’s death in 2006, I have seen scientists move from cautious optimism to optimism and now to genuine optimism.

At the 7th Annual HD Therapeutics Conference last week in Palm Springs, CA, I observed how many of the world’s leading HD researchers are preparing for clinical trials of remedies that could prolong and improve the lives of patients – and prevent me from becoming symptomatic. Notably, this year’s conference included many pharmaceutical companies: Alnylam, Isis, Medtronic, Novartis, Pfizer, Sangamo BioSciences, and Vertex.

As I participated in the conference, I felt hope come alive for the HD community.

Scientists pushing forward

I witnessed hope in the scientists’ confident smiles, animated conversations, and enthusiastic handshakes – including that of Dr. Robert Pacifici, the chief scientific officer of CHDI Management, Inc., the multi-million-dollar HD treatment initiative and the organizer of the conference.

Dr. Robert Pacifici (left) and Gene Veritas

“There are now eight things with the potential to reach the clinic in a two-year time horizon and a bunch more behind that,” Dr. Pacifici told me in an interview.

I also encountered optimism in Dr. Jim Gusella, whose research team found the general location of the HD gene (the marker) in 1983 and, in 1993, cloned it, making possible a simple, 100-percent accurate genetic test for the disease.

In many ways, his historic work laid the foundation for today’s advances. His current work includes the search for modifier genes – genes that, in addition to the HD gene, might affect the onset of the disease.

But scientists require an engaged HD community. In an interview, Dr. Gusella told me that patient participation is “incredibly important” in the drive for treatments.

“You cannot study a human disease without studying the people who have the human disease,” he explained. “You can’t test a drug unless you have people to test it on to see whether it does anything. The more they can participate, the better, whether it’s just giving a blood sample or going in and having neurologic exams to look at progression of disease or participating in a clinical trial.”

And, Dr. Gusella added, the community must maintain hope.

Dr. Jim Gusella (left) and Gene Veritas

Lowering huntingtin

Above all, I saw hope personified in the conference’s two dozen presentations and nearly 100 posters – all of them focused on the goal of understanding HD more deeply and/or developing treatments.

As I strived to process the vast information of this highly compressed 72-hour event, I felt exhilarated at the prospects of being freed from the threat of HD.

I paid special attention to the sessions on “lowering huntingtin,” a variety of strategies for reducing the amount of defective protein in brain cells. These strategies seek to block HD at its genetic roots, thus ameliorating or preventing symptoms.

I’ve followed one of these initiatives, a collaboration between CHDI and Isis Pharmaceuticals, Inc., since early 2008 (click here to read more).

I was thrilled to watch Dr. Frank Bennett, the Isis senior vice president of research, present an update . This year or next, Isis likely will apply to the federal Food and Drug Administration for a Phase I clinical trial to test the safety of its “antisense” technology, a class of substances known as “oligonucleotides,” or “oligos,” which would interrupt the production of defective proteins.

Isis, CHDI, and academic collaborators such as the HD lab of Dr. Michael Hayden at the University of British Columbia achieved an important breakthrough by discovering a way to lower defective huntingtin proteins while allowing normal huntingtin to carry on its vital tasks in the brain cells.

Isis has demonstrated the feasibility and safety of lowering huntingtin in mice, rats, and non-human primates.

Significantly, the Isis oligos have helped alleviate symptoms in HD mice.

An excellent scenario

Sitting cross-legged on the floor in front of the podium, I snapped photos of Dr. Bennett’s slides and listened intently to each word.

It was like having a front-row seat at a grand theatrical production – but one that was about me and the hundreds of thousands of people around the world affected by HD as patients or gene-positive people awaiting onset.

Dr. Frank Bennett (right) and Gene Veritas (photo by Dr. Ed Wild)

We wait as the actors, these scientific heroes, unravel the plot towards effective treatments.

“CHDI like a dream – couldn’t have imagined a better scenario,” I wrote in my notes. “Incredible vision with gene silencing.”

(Later this year I plan to pay my fourth visit to the Isis labs in Carlsbad, CA, to prepare a detailed update on the project.)

Inspiring connections

As we depend on the scientists literally to save us from HD, they also depend on the HD community for inspiration.

In remarks to the audience, Dr. Ladislav Mrzljak, CHDI’s director of neuropharmacology, recalled my 2011 CHDI keynote speech. Dr. Mrzljak told me personally that my speech had inspired him as he assumed his new role at CHDI after eleven years at the pharmaceutical giant AstraZeneca.

After one speaker noted that a researcher at my alma mater, Yale, had received a CHDI grant, I asked Dr. Mrzljak for details. Not only did Dr. Mrzljak personally know the researcher; he himself had spent the 1990s at Yale studying with world-famous cognitive neuroscientist Patricia Goldman-Rakic.

Dr. Mrzljak presented evidence that a CHDI-designed compound (CHDI-246) produced positive effects as measured in brain samples taken from HD mice. Research on CHDI-246 continues.

Dr. Ladislav Mrzljak (photo by Gene Veritas)

In addition to scientific veterans, this year’s conference included many young poster presenters. I met Julie Harness, a Ph.D. student specializing in HD stem-cell research at the University of California, Irvine (UCI).

Using both normal and HD-affected embryonic stem cells derived from discarded blastocysts from couples who opted for pre-implantation genetic diagnosis, Harness seeks to understand the causes of HD and perhaps develop an approach to treatment, including drug discovery. (Click here for more on California’s HD stem-cell-research. In a future article I will explore UCI’s HD research in depth.)

Harness told me that she felt inspired to present a poster this year after seeing photos of posters from last year sent by another UCI graduate student who had attended the 2011 meeting. Perhaps I took those photos – because I have included poster photos in this blog and since 2010 have supplied CHDI with a CD containing photos of all posters.

Julie is also a reader of this blog.

Julie Harness and her poster on a stem-cell drug-discovery platform for HD (photo by Gene Veritas)

Coming down to the wire

Despite the positive outlook, participating in the conference also magnified my fears of onset. My mother’s symptoms apparently began in her late 40s. At 52, I count each day without the classic symptoms – chorea (shaking), cognitive loss, and mood disorders – as a bonus.

I wondered: will the clinical trials prove successful, and will the medicines come in time to save me? If I become ill, will they help me recover?

As I watched Dr. Sarah Tabrizi’s slides demonstrating significant changes in the brain before classic onset, my heart sank. She stated that these changes begin as early as 20 years before predicted onset.

I glanced over at Jeff Carroll, a recently minted Ph.D. who is emerging as a leader in HD research. His poster – a study of HD mice and cell metabolism that suggests another potential approach to treatment – won first prize. Dr. Carroll, 34, is also gene-positive for HD and, like me, places great hope in the Isis project. His research has contributed to that project.

Dr. Jeff Carroll ponders Dr. Bennett's Isis update (photo by Gene Veritas).

“We’re fried!” I thought to myself as I viewed images of the brain shrinking.

To my relief, Dr. Tabrizi pointed out that, despite significant changes in the brain, “premanifest” individuals maintain an almost normal level of cognitive abilities.

“Despite striking brain changes, premanifest HD gene carriers did not deteriorate significantly over 24 months in cognition or motor function tasks,” she said in reference to the TRACK-HD study that she headed. “I think that tells us that the brain is functionally plastic and is compensating. And the good news is that there may be a lot to rescue.”

“We gene positive are really coming down to the wire!” I wrote in my notes. “Can we hold on??? If I get sick, can I recover with meds? Evidence in mouse trials suggests: yes!”

The first dose

I shook many hands at the CHDI meeting – perhaps even the hands of those who will produce the first effective treatment to stop HD symptoms.

After the conference, we have all returned to the HD trenches.

The scientists must now turn hope into actual treatments.

I must continue my work as an advocate for the Huntington’s Disease Society of America (HDSA).

My task is to carry the message of hope of a treatment to everybody I encounter in the HD community, either in person or online.

Indeed, this must become the priority of HDSA and advocates everywhere.

In an HD treatment, the first dose is hope.

Gene Veritas and CHDI's newly launched logo. Dr. Simon Noble, CHDI’s director of scientific communications, explained to the audience that the new logo symbolizes CHDI as a “drug development organization” seeking “effective treatments” as its first goal. The tree represents the biology and chemistry involved in HD and HD research, clinical developments, neurons, biological pathways, and the hereditary nature of HD. The logo's muted color reflects the “somber nature” of CHDI’s mission. While the initials “CHDI” once referred to “cure Huntington’s disease initiative,” the foundation emphasizes that the initials no longer signify that phrase. "We can worry about curing down the line, however you want to define curing," Dr. Noble stated. (photo by Lev Blumenstein)

(In a future article I will examine the research progress reported at the CHDI conference.)

Thursday, March 01, 2012

Top researcher: ‘Genuine optimism’ about treatments for Huntington’s disease

With several potential treatments heading for clinical trials, the head researcher of the so-called “cure Huntington’s initiative” feels “genuine optimism” about alleviating the devastating symptoms of this incurable, fatal brain disorder that also affects other areas of the body.

“People ask me all the time, ‘Are you optimistic?’” said Dr. Robert Pacifici, the chief scientific officer of CHDI Management, Inc., the virtual biotech firm dedicated exclusively to ending HD. “I am. I really am. I’m genuinely optimistic.”

CHDI Management is the research arm of the CHDI Foundation, Inc., the multi-million-dollar initiative backed by a group of anonymous donors.

Dr. Pacifici made his comments in an interview with me during CHDI’s 7th Annual HD Therapeutics Conference at the Parker Palm Springs hotel in Palm Springs, CA, February 27-March 1.

Representing both academia and drug companies, the approximately 200 scientists and observers at the conference were abuzz with the promising developments presented by their colleagues in the formal part of the program.

When he expresses optimism, Dr. Pacifici told me, “the HD community doesn’t let you get off easy. They say, ‘Why?”

He outlined three major reasons for his optimism.

First, CHDI and the HD research community have “a large number of shots on goal” in terms of potential treatments.

“There are now eight things with the potential to reach the clinic in a two-year time horizon and a bunch more behind that,” Dr. Pacifici said.

(Scientists do not predict the outcomeof trials nor the date at which an effective treatment will be found.)

Secondly, he stated that researchers will test each compound under study so as to obtain “an unambiguous result.” This will permit the researchers to quickly evaluate the results and, if necessary, adjust the compounds.

Third, Dr. Pacifici pointed out that the potential treatments are “custom-crafted” for Huntington’s disease.

Researchers know that potential drugs must to enter the brain, be taken for a long time, and not present serious negative side effects, he explained. By making the drugs HD-specific, the researchers can meet these challenges.

Future articles will explore the results of the conference and specific treatments in greater detail.

You can my watch the interview with Dr. Pacifici in the video below. Also visit www.hdbuzz.net.