The Holy Grail of Huntington's disease research: the gene-positive, drug trials, and treatments

Living in the gray zone between my genetic test for Huntington’s disease and the inevitable but indefinite onset of this devastating brain disorder, I frequently feel forgotten in the excited discussion about impending clinical trials to test potential treatments.

HD researchers want to include people like me in trials, but haven’t yet found a way to do so.

I am a victim in waiting, but without any of the noticeable, classic symptoms that would qualify me for participation in a clinical trial.

Because so much of the effort against HD is geared to helping the affected and the caregivers, I sometimes sense that we, the asymptomatic (or pre-manifest) gene-positive, have been relegated to second priority.

Emotional impact

I recognize that I am, for the time being, relatively fortunate, but the situation of perceived neglect, although unintentional, impacts me emotionally.

I wonder if symptomatic people feel jealous towards me – just as I have occasionally reacted with a furious inner jealousy when I learn that someone has tested negative. In other instances, I have briefly felt smug when I’m around or am thinking about people with symptoms.

In yet other instances, I feel compassion – and even profound guilt. I tell myself, “You have no right to worry! You’re not even sick! Your life hasn’t even been affected by the disease!”

Mostly, I just feel lucky to function normally and to have the opportunity to enjoy daily life.

But then I remember, “Yes, I have been affected by this disease. It took Mom’s life at only age 68, and it has robbed me and my family of so many dreams.”

I literally dreamt about my status last night as my mind worked on this article: a team of HD medical specialists put me through a series of exams to see whether symptoms had begun, and, as I awaited the results, I used a large red marker to edit this text.

Not coincidentally, it’s time to set up my annual checkup at the Huntington’s Disease Society of America’s Center of Excellence for Family Services and Research at the University of California, San Diego.

So far, those checkups have not turned up any of HD’s classic, outwardly noticeable symptoms.

But I am hyper-conscious of the fact that HD affects the brain ten or more years before those symptoms start. If an effective treatment isn’t found in the next few years, I will be doomed to follow in my mother’s footsteps.

Unable to reach the finish line?

The feelings of vulnerability and abandonment are magnified when I remember that no current or impending HD clinical trial includes participation of those of us who are pre-manifest.

In short, everything is currently focused on stopping HD already in progress. Nobody has yet developed a workable strategy for preventing the onset of HD.

Along with the scientists I have interviewed over the years, I am confident that a significant treatment or series of treatments will become available in the next decade or so to ameliorate the symptoms. Of course, I also hope for a “cure,” but scientists don’t use that term. They talk of controlling or managing the disease, because, of course, the defective HD gene cannot be removed from the body.

But I’m deeply worried that scientists will still take many more years beyond that to discover treatments for people like me, treatments that can stave off onset and/or minimize symptoms.

Ever since I tested positive in 1999, I have been racing against my own interior genetic clock to avoid symptoms and support the HD movement.

But the probability that my symptoms will start in the next few years leaves me with the sensation of the marathon runner who glimpses the finish line but ultimately cannot reach it.

Participation in studies

For now, pre-manifest people can participate in research studies. Whereas clinical trials aim specifically to test the safety, tolerability, and efficacy of a drug, studies seek to provide further information about a disease and/or strategies for treating it.

Studies can also include a test of safety and tolerability of a substance, as exemplified in the PREQUEL study, an investigation of coenzyme Q-10 exclusively in a pre-manifest group of 90 individuals. PREQUEL also aims to “assess the usefulness of certain markers of HD in the blood, which may help measure the rate of the disease progression or effects of medication.” Its coordinators aim to use it as precursor to a clinical trial of coenzyme Q-10, an antioxidant produced in the brain and that has led to the improvement of symptoms in HD mouse models.

Major studies involving pre-manifest people include PREDICT-HD, COHORT, and the forthcoming Enroll-HD, a new, worldwide HD database expected to start gathering information in early 2012. (Click here to read my previous article on Enroll-HD). Enroll-HD is sponsored by the CHDI Foundation, Inc., the so-called “cure Huntington’s disease initiative,” a multi-million-dollar effort backed by a group of anonymous donors.

Through the above-mentioned Center of Excellence, I have participated in a number of studies, including COHORT, MRI studies, research involving HD and the sense of smell, and an experiment with instruments designed to measure loss in mobility. (Click here and here to read more.) I have also given blood and, for many years, participated in cognitive batteries and a Dementia Rating Scale study. I also took part as the only pre-manifest individual in the Huntington’s Disease Drug Works program’s "treatment now" observational trial of supplements, a rare opportunity for someone in my situation.

A ‘long time’ to gene-positive trials

The federal Food and Drug Administration (FDA) will not permit pre-manifest people to participate in clinical trials until beneficial results have first been demonstrated in symptomatic patients. The FDA also requires that researchers come up with useful ways to measure benefits in the pre-manifest.

I became acutely aware of the challenges of designing a drug for the pre-manifest during a July 2009 interview with Dr. Frank Bennett, the senior vice president for research at Isis Pharmaceuticals, Inc., in Carlsbad, CA. Along with CHDI, Isis is planning a clinical trial of a revolutionary drug that, if successful, would attack HD at its genetic roots and slow or perhaps even stop the progression of the disease in the brain.

Dr. Bennett told me that although the clinical trial will focus only on symptomatic patients, he was “optimistic” that a way could be found to help the pre-manifest, too.

Exhilarated by the promise of a potential “cure,” I wrote several enthusiastic articles about Isis.

But privately I also felt somewhat desperate, because, as Dr. Bennett explained, finding a solution for the pre-manifest would take a “long time.”

“Identifying when to start treating those patients is going to be a little tricky, as you might imagine, because you don’t want to do it too soon,” he said. By the same token, Dr. Bennett added, waiting too long would miss the opportunity to protect brain cells, which, once damaged, could not recover. “This is not a short-term fix but it’s something that’s going to take a large number of years to figure out how to optimally treat these patients.”

Other path-breaking clinical trials face similar hurdles. Alnylam Pharmaceuticals, which is close to starting its own clinical trial for a similar attack on the disease’s genetic causes, plans to inject its drug directly into the heads of patients, but they must first undergo an operation so that a very fine needle can be inserted into their brains (click here to read more). Medically, scientifically, and ethically speaking, only symptomatic patients can undergo the many risks of such a trial.

As Dr. Bennett and others have noted, the FDA will display great caution with these new kinds of drugs as well as the highly invasive delivery systems. Isis and Alnylam are striving to minimize levels of risk and invasiveness.

Seeking the Holy Grail

HD researchers face a major challenge in finding a treatment for the pre-manifest. It’s really the Holy Grail not only for HD, but also for other neurological diseases such as Alzheimer’s in which brain damage occurs many years before symptoms appear. Ideally, researchers want to design medications that will completely prevent these diseases.

In a recent e-mail to me, CHDI President Robi Blumenstein elaborated on this point with an analogy.

“The purpose of a cholesterol-lowering drug is to prevent heart disease, not lower cholesterol for its own sake,” he explained. “Cholesterol-lowering drugs were tested on people at risk for heart disease. By analogy, we would like to test HD drugs on gene-positive people (like you) at risk of developing symptoms of HD to see if the intervention prevents the appearance of symptoms (that is, slows or arrests the progression of the disease).”

So, as researchers ramp up to clinical trials, this challenge is gaining greater attention. At the World Congress on Huntington’s Disease in Melbourne, Australia, in early September, several scientists revealed their research into areas directly related to this challenge, including a study of brain changes in the pre-manifest, the development of measurements from MRI brain scans to predict and track symptoms, and a report on how functional MRI scans can detect brain activity changes before brain shrinkage occurs. (For details click here.)

In his remarks at the World Congress, Blumenstein pointed out that researchers need both gene-positive and affected individuals to participate in research studies now in order to prepare adequate measurement tools for clinical trials.

“It would be a shame if we have potential drugs to test but lack the tools to conduct the tests to see if they are having the desired effect,” Blumenstein wrote to me.

“What the FDA will accept for regulatory purposes (i.e., to approve a drug) and whether we can satisfy ourselves that we are on the right track scientifically to modify the disease are two different questions,” he added. “We will need people like you to participate in studies and, yes, trials to establish the latter. When we are successful with that the former may require some education and lobbying of the regulators to convince them that new approaches to approving drugs for genetic diseases are appropriate.”

Waiting in the wings

For the beleaguered Huntington’s disease community, clinical trials of potential treatments provide a ray of hope.

Looking back to my mother’s diagnosis in 1995, I recognize that researchers have made stunning progress. But big hurdles remain, especially in developing preventive treatments for the pre-manifest.

I share the researchers’ optimism, but I temper it with a sober assessment of the complexity of the challenges.

For me, time is ever more precious.

Once again, it’s crystal clear that researchers ultimately rely on the participation of HD-affected families. Everybody can play a part – the untested at risk and the pre-manifest in research studies, and the affected in clinical trials.

The affected will bravely pioneer treatments by initiating the trials.

For the time being, however, gene-positive individuals like me must wait in the wings.

But we can assist immensely by supporting the affected, advocating for the cause, and, perhaps most importantly, taking part in the appropriate studies and experiments.

Together we dream of the day when we can all declare: “I’m HD-free!”

Today, being gene-positive for Huntington’s disease threatens the well-being of me and my family. But if the science continues to accelerate, it will provide hope that carrying the HD gene will become little more than an inconvenience.

BDNF and ‘Neurobics’: building a ‘beautiful mind’ against Huntington’s

To avoid the onset of Huntington’s disease, whose killer gene I inherited from my mother, I must do all I can to protect my brain.

In 2001, two years after testing positive for HD, I was inspired by the film A Beautiful Mind to try to think my way to cerebral health. In that film, starring Russell Crowe and Ed Harris (two of my favorite actors), the true-life figure of Nobel Prize-winning mathematician John Nash used his intelligence to distinguish the hallucinations of his schizophrenia from reality and to regain a normal life.

In effect, Nash tricked his symptoms.

I didn’t believe that I could trick HD. Like schizophrenia, HD is a brain disorder, but with far more devastating symptoms – and without a treatment for its root causes. Schizophrenia can be controlled with medication. HD cannot. And, whereas the causes of schizophrenia are thought to be a combination of genetic and environmental factors, HD is completely genetic, with 100 percent of gene-positive individuals eventually becoming symptomatic.

Tricking a gene like that seemed impossible.

Working the brain to exhaustion

But I did believe that keeping an active mind, thinking positively, and working for a cure for HD might allow me to delay onset.

My job as a college professor already provided wonderful stimulation for my brain. I read, wrote, traveled, and lectured regularly. Contact with the young, vibrant students kept me feeling young myself.

As a member of the board of directors of the San Diego chapter of the Huntington’s Disease Society of America (HDSA-San Diego), I took on the hugely stimulating, and time-consuming, task of writing, editing, and producing the organization’s tri-annual newsletter. Using skills gained in my former work as a journalist and my current career as a historian, I delved into the harsh reality of HD as well as the growing body of scientific research towards treatments and a cure.

I ran the newsletter until 2007. During that time, I watched my mother rapidly decline and ultimately die of HD in early 2006, and I rode the emotional roller-coaster of wondering and waiting about the onset of my own symptoms.

I had purposely over-stimulated my brain – many times to the point of exhaustion.

A self-fertilizing garden

In the mid-2000s, I began reading about a new discovery about HD and the brain that provided me with another tool to build my “beautiful mind” against onset: I could increase the amount of a crucial substance for brain health known as BDNF (brain derived neurotrophic factor) by exercising.

A nutrient, BDNF acts like fertilizer for the brain. It is produced in the cortex, the convoluted, outer hemispheres of the brain, and transported into the striatum, the inner, lower level of the brain. Thus, in the words of researchers, our brains function like “a self-fertilizing garden.”

The striatum happens to be the area of the brain most affected in Huntington’s disease. Starting in the early 2000s, scientists working with HD mouse models observed that BDNF levels fell dramatically in the striatum. The lower the amount of BDNF in the mouse brains, the earlier and more severe was their HD onset.

“The promising new findings about BDNF can be exploited even today,” wrote Dr. Marsha Miller on the Huntington’s Disease Lighthouse Family website in 2006 (click here to read more). “There are easy, cheap, reasonably safe ways for people to increase BDNF levels in the brain. Exercise, maintaining a reasonably low weight, and enjoying a stimulating, but not overly stressful, social and mental life all raise BDNF levels. Other BDNF enhancers include the antidepressants known as selective serotonin-reuptake inhibitors (SSRIs), such as sertraline, and a few other drugs.”

This was excellent news for all gene-positive and symptomatic HD people. We could actually increase BDNF in our brains and therefore perhaps delay the onset of the disease or slow down the progression of symptoms!

A hot topic

BDNF was a hot topic at the 2011 Sixth Annual HD Therapeutics Conference from February 7-10, 2011, in Palm Springs, California. In addition to keynoting this meeting, I reported on the scientific presentations. The event was sponsored by the CHDI Foundation, Inc., the so-called “cure Huntington’s disease initiative,” a multi-million-dollar program backed by anonymous donors.

In his presentation on brain receptors that link up with BDNF, Dr. Moses Chao of the New York University School of Medicine observed that research shows that the lack of the substance helps cause the neuropsychiatric symptoms of HD (such as depression).

BDNF, he observed, contributes to a number of important activities in the brain, including the development of the cytoskeleton (the skeleton of the cell) and the ability of the synapses to adjust their strength. BDNF also helps cells survive.

As Dr. Chao pointed out, scientists first thought it might be possible to inject BDNF directly into the brain to help patients. However, in their experiments they encountered difficulties in delivering the BDNF, and it proved to be very “sticky,” meaning that it did not move easily in the brain. There were also negative side effects.

More recently, Dr. Chao explained, scientists have sought ways to bypass these problems. That research has focused on the BDNF receptors, molecules in the brain that link to BDNF so that it can carry out its tasks. Scientists are also examining substances that can bind to the receptors and act as a substitute for BDNF.

There may be other ways to raise the amount of BDNF. Dr. Allan Tobin of CHDI, for instance, has conducted a workshop to investigate the use of molecules that could mimic the effect of exercise on the brain and therefore increase BDNF levels.

For further details on the importance of BDNF and the research efforts towards BDNF-based HD treatments, watch the short video below by Dr. Jody Corey-Bloom of the HDSA Center of Excellence for Family Services and Research at the University of California, San Diego.



For additional background on BDNF, visit the Huntington’s Disease Lighthouse Family. Also see the report on the CHDI meeting at HDBuzz.

For the latest in HD stem-cell research and BDNF, watch the video below by Dr. Jan Nolta, Professor in the Department of Cell Biology and Human Anatomy and Director of the Stem-Cell Program at the University of California, Davis.



Thinking about exercise

To increase my own BDNF, I exercise regularly.

In 2009, when my wife and I decided to build a pool in our back yard, I installed a Fastlane swimming device that creates a powerful current against which I swim. Weather and time permitting, I try to swim 30 minutes three to five times per week.

I try to vary my exercise routine at least a bit. A few years ago, I went through a cycling phase. At times I also have used an elliptical machine for cross-training of the arms and legs.

Now I alternate swimming with 30- to 40-minute walks with my dog Lenny, a three-year-old male cockapoo full of love and energy.

I read once that, in order for exercise to provide maximum benefit for the body, the individual must think about the exercise while he or she is performing it.

So, for example, I don’t listen to music when walking. And I stopped using the elliptical while watching television.

While swimming in recent months, I have imagined BDNF bathing my brain. In my mind, as I stroke against the current, I sometimes chant a mantra: B-D-N-F.

As I wrote in my blog notes the other day, for me BDNF signifies “beautifully derived neurotrophic factor.”

Breaking the routine

After my September 21, 2011, entry titled “Waiting for symptoms: How long can I hang on?”, Dr. Chao wrote me an e-mail encouraging me to work on increasing my BDNF levels “through increased exercise or any other kind of novel activity (travel, learning a new language, etc.).”

I asked Dr. Chao to comment on a recent study that had left me puzzled and worried after I read about it during the summer. Investigators at the National Institutes of Health found that a particular kind of transgenic HD mouse, living in a cage where it could use a running wheel, became symptomatic earlier, had more severe impairments, and suffered greater damage to the striatum because of exercise!

Dr. Moses Chao at the 2011 CHDI HD Therapeutics Conference (photo by Gene Veritas)

“The article on the detrimental effects of exercise was carried out with a transgenic HD animal model that has not been well studied,” Dr. Chao responded. “I suspect it develops some pathology early on that might interfere with exercise. One issue about exercise is it helps if there is novelty. Routine activity (‘running wheels’) can be brain-deadening.”

Dr. Chao’s comments drove home two points: I needed to vary my exercise and personal enrichment and to enjoy them fully. I must not view the avoidance of onset as an obligation or chore, but as life-affirming.

Neurobics: a way to increase BDNF

Dr. Chao followed up by mailing me a copy of a book by the late neuroscientist Lawrence C. Katz, Ph.D., and writer Manning Rubin titled Keep Your Brain Alive: 83 Neurobic Exercises to Help Prevent Memory Loss and Increase Mental Fitness.

“Neurobics” combines the words “neuron” and “aerobics.”

Many people are familiar with the standard recommendations for giving the brain a workout: crossword puzzles, logic puzzles, reading, memory exercises, and engaging with interesting people and “other kinds of challenging activities that exercise brain circuits in different ways,” write Katz and Rubin.

They recommend that people continue with such activities.

But they should also practice the very different kind of exercises involved in Neurobics. These simple mental exercises serve as cross-training for the brain.

“Neurobic exercises use the five senses in novel ways to enhance the brain’s natural drive to form associations between different types of information,” write Katz and Rubin. “Associations (putting a name together with a face, or a smell with a food, for example) are the building blocks of memory and how we learn. Deliberately creating new associative patterns is a central part of the Neurobic program.”

And they add a point of the utmost importance for for HD-positive and HD-affected individuals: it’s well-established that Neurobic exercises increase levels of BDNF!

“In short, with Neurobics you can grow your own brain food – without drugs or diet,” Katz and Rubin state. “The more active brain cells are, the more growth-stimulating molecules they produce and the better they respond.”

Trying the exercises

Katz and Rubin begin with the example of a simple but powerful stimulant to the brain: when you arrive home at the end of the day, rather than relying on your sense of sight, close your eyes and use your senses of touch, hearing, and smell to guide you into the house.

Another exercise, which I tried yesterday, is to brush your teeth with the opposite hand. For a right-handed individual like me, this stimulates the less-used right hemisphere of the brain.

When I walked Lenny the other day, I followed the book’s suggestion of taking a different route. I sensed it was more stimulating for him, too.

Lenny and I leaving on one of our frequent walks

“It’s rather astounding when you think about it,” Katz and Rubin observe. “A certain kind of sensory experience can permanently change the wiring in part of your brain!”

They conclude: “Neurobics uses an approach based on how the brain works, not simply on how to work the brain.”

Everybody in the HD community (and everybody else, for that matter) should read Keep Your Brain Alive. It provides a treasure trove of information about how our brains work and how to protect them from disease and aging.

Quality, not just quantity

When I first learned of HD because of my mother’s diagnosis in 1995, doctors and researchers told me there was virtually nothing an at-risk or gene-positive person could do. HD symptoms are inevitable.

Since then, scientists plumbing the depths of the brain and diseases such as HD have turned up evidence to the contrary.

I wrote in my notes the other day: “YES!!! There are things we can DO to help our brains stave off HD!”

Neurobics may not prevent me from becoming symptomatic, but it very possibly could delay onset and, when it occurs, reduce the devastation of my brain.

From my contact with Dr. Chao, I have learned that I must focus not only on the quantity of exercise, but its quality. I need to stop frantically overstimulating my brain and instead concentrate on exercise, Neurobics, and other activities that will increase my BNDF.

As Katz and Rubin point out, that includes maintaining a rewarding emotional life based on intimate connections to people.

Living neurobically

For my survival, nothing could be more important than exercise, cross-training my brain, and strengthening ties to family and friends.

Although the hope of treatments has increased dramatically, chances are that a treatment will not become available before my symptoms start.

Through HDSA and this blog, I’ve fought for the success of the HD movement. Soon the moment may come when I will need to focus just on me and my own brain, living my final days of mental clarity as neurobically as possible.

Some reflections on being named 'HDSA Person of the Year'

With a feeling of great humility and immense responsibility I received the news that the Huntington’s Disease Society of America (HDSA), at its national convention on June 25 in Minneapolis, had named me the 2011 HDSA Person of the Year.

As I wrote here on June 21, I was excited about attending an HDSA convention for the very first time. Alas, that same day I came down with a fever and nasty sinus infection and could not travel.

I did not know about the award. At home recovering, I happened to check e-mail on the night of the 25th. I was stunned! Several messages stated that I was receiving the award and that the announcement prompted a standing ovation. (A record 1,000-plus people attended the convention.)

Don Barr, the chairman of the HDSA Board of Trustees, and Louise Vetter, CEO, presented the plaque, accepted in my absence by trustee Rob Millum, my friend and also a member of the HDSA-San Diego board.

An award for inspiration

HDSA gives this award “to someone who has been an inspiration to others,” Barr told the audience at the HDSA closing ceremony. He noted my work as a member of the HDSA-San Diego board, gene-positive blogger, stem-cell research advocate, and speaker at biotech companies.

Above, Don Barr (left), Rob Millum, and Louise Vetter with my plaque (photo by Ashley Miller). Below, a detail of the plaque (click on image to see larger view) (photo by Gene Veritas).



Barr stated that I had “given a face to this often faceless disease” and “inspired countless individuals who are at risk or gene-positive to express themselves without fear and to let them know that they are not alone in the face of HD.”

For those who fight

Shana Martin, the HD activist, top athlete, and model, posted a note of congratulations on my Facebook page, as did friends and acquaintances in the HD community.

“I am stunned and flattered to receive this recognition, and sad that, because of illness, I could not attend the convention,” I responded to these notes. “I want to remember my mom Carol, who died of HD in 2006, and my ‘HD warrior’ father Paul, her caregiver, who died in 2009. The honor is for the battle they fought – and for the battle that our entire community fights each day.”

On that night, I deeply missed Mom and Dad. They would have been proud of me. I felt sorrow that the collective efforts of HDSA, researchers, and advocates like me had not produced a treatment in time to save Mom, who died at the age of 68 after battling HD for more than 15 years.

My parents, Paul and Carol, in January of 2004 (photo by Gene Veritas)

I know, too, that this award is not just for me, but for everybody affected by HD: the at-risk, the gene-positive, the symptomatic, the families, and the unsung heroes of America, the caregivers.

And I have huge shoes to fill in the HDSA Person of the Year tradition, which stretches back more than ten years.

Here’s a list of past awardees, in reverse chronological order: 2010, Katie Moser; 2009, Kris O’Brien; 2008, Bob Leck; 2007, Frank Hiscock; 2006, Gary Nash; 2005, Bruce Veneklase; 2004, Bryan Medrano; 2003, Karen Milek; 2002, Gary Elliott; 2001, Phil Hardt; 2000, Marc Church.

A new departure

For me, the Person of the Year Award is not an endpoint, but a new jumping off point.

As Don Barr noted in making the presentation, I long worked behind the scenes for the HD cause. In 2010 and 2011, however, I began exiting the “HD closet” by giving several speeches, going on the radio, and posting videos of myself on the web.

I hope to use the award’s prestige to build even greater awareness about HD and to encourage the research community to redouble its efforts in the search for treatments and a cure.

I especially hope that I can use this award to combat the stigma surrounding HD and other neurological diseases.

Time for leadership

I’ve reached a stage in the cause, and in my life as a gene-positive person, when I must exercise leadership.

I must get back in the HD trenches to continue my fight as before. I cannot shy away from new challenges such as the need to help prepare the HD community for potential clinical trials for the possible drugs now in development in labs. (On July 30, I’ll be speaking on this topic at an HDSA symposium in Seattle.)

Convention participants at the closing ceremony (photo by Ashley Miller)

Leadership takes place on many levels and in many venues of life: family, work, community, religious organization, advocacy, and politics.

Everybody can lead in his or her own unique way. All of us in the HD community must play our part to strengthen our movement.

I’ll be with you, shoulder-to-shoulder, as we work for better care and seek the cure.