Deciphering signals from Huntington’s disease brains in the search for treatments

From coast to coast and around the world, scientists like Andrew F. Leuchter, M.D., and Michael Levine, Ph.D., are engaged in the quest for Huntington’s disease treatments.

During May, Huntington’s Disease Awareness Month, I want to call attention to the critical work of Drs. Leuchter and Levine on the West Coast. They exemplify the partnership of scientists and physicians with the HD community, aiming to advance potential remedies into crucial clinical trials.

Drs. Leuchter and Levine, faculty researchers at the renowned Semel Institute for Neuroscience and Behavior at the University of California, Los Angeles (UCLA), are collaborating on a project that could ultimately lead to new drugs. In the near term, they aim to understand more fully the electrical signals that naturally but abnormally emanate from the brains of HD patients and presymptomatic carriers of the HD gene mutation like me.

“Most of the brain’s energy goes to creating electrical gradients – electrical impulses – but we haven’t been very good at using that for diagnosis and treatment,” Dr. Leuchter said during a March 20 interview in his office at the Semel Institute. He and Dr. Levine aim to “decipher the signals that are coming out of the brain.”

The Semel Institute for Neuroscience and Behavior (photo by Gene Veritas)

Measuring brain energy

A psychiatrist specializing in depression and Alzheimer’s disease, Dr. Leuchter (pronounced LUKE-ter) frequently employs quantitative electroencephalography (quantitative EEG) to measure the energy emitting from people’s brains. One example: a group of 27 HD subjects he and others observed for a study published in 2010 and funded by CHDI Foundation, Inc., the nonprofit virtual biotech dedicated exclusively to the discovery of HD treatments.

Allan Tobin, Ph.D., at the time the head of UCLA’s Brain Research Institute and a senior scientific advisor at CHDI, had asked colleague Leuchter for assistance in finding HD biomarkers, signals that reveal the progression of the disease and/or the effectiveness of a medication.

As the number of HD clinical trials expands exponentially, the search for useful biomarkers has become one of the hottest areas in Huntington's disease research. (Click here to read about one new potential biomarker.)

As Dr. Leuchter pointed out, neurological and psychiatric disorders are “much more limited in diagnostic tests for the organ that we are studying than any other branch of medicine.” Cardiologists insert catheters into the heart, and gastroenterologists use scopes to view the stomach and intestines.

“If you’re a psychiatrist, we talk to people, which is great, but we don’t have physiologic tests that guide decision-making,” he added.

Scientists and doctors rarely put electrodes in living human brains or take biopsies of brain tissue. However, they have been measuring brain energy with EEGs for more than a century, Dr. Leuchter explained.

As he demonstrated in his lab (see photo below), today patients undergoing testing wear a cap with 35 separate EEG electrodes, or contacts, that touch the head. The attending researcher stretches the cap over the patient’s head. In contrast with the traditional EEG, which involves one-by-one placement of the electrodes on the head, this method is quick, efficient, and less burdensome to patients, he noted.

Above, Dr. Andrew Leuchter points out the electrodes on the EEG cap worn by research subjects. Below, he explains digitized EEG readings displayed on a computer monitor. (photos by Gene Veritas) 

“We find that this helps to standardize our measurements of brain activity, and that we can place the electrodes in about 15 minutes,” Dr. Leuchter said.

EEG is inexpensive, convenient, and easy to administer. Additionally, it does not expose patients to radiation or require them to lie inside a machine such as an MRI scanner, he noted.

“You can tote it wherever you like,” he said of the EEG device.

The brain’s pacemaker

As they had hoped, Dr. Leuchter and three other UCLA researchers discovered abnormal EEG readings in HD patients with just mild symptoms.

“But the really intriguing thing there was that, even in people who were gene-positive but premanifest, we could see differences in brain function estimated 15, 20 years out from diagnosis,” Dr. Leuchter said, referring to signals of future decline. “So we thought this could be something that could be useful for treatment development.”

As Dr. Leuchter explained, “the brain like the heart has pacemakers.” Healthy brains produce lots of high-frequency waves. Brain illnesses commonly result from changes in the firing of the pacemaker, resulting in a greater quantity of low-frequency waves.

“What we found is that years before people start to show symptoms with Huntington’s, they’re producing more low-wave energy,” Dr. Leuchter said. “So it’s a very subtle indicator that the pacemaker of the brain is starting to slow down.”

Scientists cannot predict the actual onset and progression of symptoms from EEG signals. However, as noted below, they did discover a correlation between the severity of genetic mutation and EEG readings.

Clear genetic impact on the brain

Furthermore, the team observed that, in contrast with healthy brains, the distribution of different types of waves across the different regions of the HD brains became more uniform. “The regions of the brain start to look more similar than different,” he explained.

Researchers have not yet discovered what this phenomenon means.

“We know that the brain has enormous functional reserve and that people call on every cognitive and emotional resource they’ve got to try to keep everything functioning at optimal efficiency,” Dr. Leuchter continued. “I don’t think we know what’s compensatory and what’s an early sign of illness.”

Reflecting on another facet of the research, Dr. Leuchter explained that, in general, brain function tests do not correlate with genetic factors.

However, he and his team did find a correlation between the degree of HD genetic mutation and the severity of the changes in the EEG readings.

“Nobody had seen that,” he recalled. “We got excited about that, and that’s what we’ve been trying to follow up on.” These findings will contribute to the search for biomarkers and treatments, as explained below.

Examining brain tissue

A neurophysiologist and veteran basal ganglia researcher, since the late 1960s Dr. Levine has studied these deep, inner parts of the brain that control such actions as voluntary movements. He began to study HD in the 1990s as genetic mouse models with HD-like symptoms became available. His lab has published more than two dozen papers about these mice.

The nuclei of the basal ganglia are significantly compromised in HD, especially in the striatum. Specifically, Dr. Levine has examined how neurons communicate with each other in the cortex and striatum at cellular and molecular levels using tissue from the HD mouse models.

One of the latest techniques for studying the cells in the HD mouse models is optogenetics, in which specific types of brain cells are stimulated with light.

“I can look very closely at mechanisms,” Dr. Levine explained. “I know which types of neurons I am looking at and how they change at a very mechanistic level.”

Michael Levine, Ph.D., veteran HD researcher (photo by Gene Veritas)

Two key goals

Melding approaches, and with the expectation of CHDI support, Drs. Leuchter and Levine now seek to answer two important questions.

The first involves comparing EEG data from both mice and humans to refine the search for biomarkers. Researchers have already made the key discovery of EEG signals common to mice and humans.

“It’s actually pretty uncommon in science that you can see a very similar signal across species, that you can see something very similar in the brains of humans and the brains of animals,” Dr. Leuchter said.

If the Leuchter-Levine project confirms the degree of that similarity, that could mean  potential drugs tested in mice could ultimately be used for human clinical trials, Dr. Leuchter observed.

The second question focuses on the testing in HD mice of a CHDI-developed compound aimed at lowering the amount of mutant huntingtin protein, the major culprit in the disease.

“If we do see a link between lowering of mutant huntingtin and change in the EEG biomarker, this could be used to develop a number of therapeutic agents,” Dr. Leuchter said. “A whole line of research could develop out of this.”

From molecule to the whole brain

Drs. Leuchter and Levine estimated the project will take two years to complete.

As Dr. Levine put it, researchers hope the CHDI-developed compound will restore the EEG signals in HD patients to normal.

Dr. Leuchter reflected on the significance of the project and his collaboration with Dr. Levine: “The fact that in something like Huntington’s disease you’ve got a protein that is affecting how the nerve cells are functioning and altering the way they produce and utilize energy – it’s really a gateway to understanding the connection between what is going on at the deepest molecular level of the cell and what we’re able to see with the brain waves the individual is putting out. We can actually potentially link everything going from the level of the gene all the way to whole-brain function.”

In another potential future project, Dr. Leuchter would like to obtain EEG readings from asymptomatic gene carriers over two to three years to better measure the changes in signals over time.

Drs. Leuchter and Levine (photo by Gene Veritas)

Participation and a positive attitude

Both researchers expressed gratitude to the HD community and fellow HD researchers for their dedication to the cause.

“There are not that many people with this illness, so people get asked a lot to participate in different studies where they’re poked or prodded or scanned,” Dr. Leuchter said. “We are very grateful to those who are so generous with their time, because without their help we could not conduct these research studies.”

Dr. Levine added that he is impressed with the “very positive and sharing attitude of the investigators who do research in HD and who are looking to help the patients.”

While interviewing these two researchers, as an individual racing against the genetic clock of HD, I was once again moved to witness the creativity and enthusiasm of scientists engaged in the quest to save affected families from the devastation of Huntington’s.

(Later this month: from the East Coast a report on Yale School of Medicine researcher Doug Rothman, Ph.D., and the mystery of the mitochondria in Huntington’s disease. Please remember during HD Awareness Month to donate generously to the Huntington’s Disease Society of America or the HD cause of your choice!)

The precious participation of the Huntington’s disease community in the quest for treatments: a report on the 2015 HD Therapeutics Conference

As long-awaited clinical trials of new drug candidates for Huntington’s disease get underway, scientists have intensified collecting information from research study participants to quickly and accurately test the effectiveness of the potential remedies.

This was a major theme of the 10^th Annual HD Therapeutics Conference, held February 23-26 at the Parker Palm Springs hotel in Palm Springs, CA. (Click here to read my initial report on science and solidarity, filed during the conference.)

The event was sponsored by CHDI Foundation, Inc., a nonprofit, virtual biotech focused solely on developing HD treatments and the largest source of private HD research funding. Backed by wealthy donors, CHDI has an annual budget of about $100 million.

“The thing that I’m keying on is what I would call human data,” Robert Pacifici, Ph.D., CHDI’s chief scientific officer, told me in an interview on February 26. “Obviously when we do drug discovery we think about a variety of model systems – everything from worms to flies to zebrafish to sheep and songbirds and everything in between.

“But we both know that the only organism that actually has Huntington’s disease unfortunately is the human. So for a long time I’ve been saying that there’s nothing more precious and valuable to a drug hunter than an observation that’s actually made in the population that they seek to treat, in our case Huntington’s patients.”

Dr. Pacifici recalled how genetic data from hundreds of people from dozens of families led to the discovery of the huntingtin gene in 1993. Thanks to those efforts, treatments aimed at lowering the amount of mutant huntingtin RNA and protein in the brain cells of HD patients are on the verge of entering clinical trials, he added.

“Now what we’re asking for is to really start getting more specific about the observations [in humans] that we want to make and how we’re going to leverage them,” Dr. Pacifici explained.

You can watch my interview with Dr. Pacific in the video below.

Human Data 'Precious' for Huntington's Disease Drug Hunters: An Interview with Dr. Robert Pacifici from Gene Veritas on Vimeo.

Key role of modifier genes

Dr. Pacifici cited two major examples of new human data revealed at the conference that will a have profound impact on the quest for treatments.

“We’re literally at the precipice of identifying what are modifier genes,” he said, referring to the research presented by Jong-Min Lee, Ph.D., of Massachusetts General Hospital. “It’s just incredibly exciting to me.”

An abnormally expanded huntingtin gene is the principal cause of HD, but other so-called modifier genes also help determine the age of disease onset.

“Why is it that one person’s Huntington’s starts earlier than another?” Dr. Pacifici asked. “That’s tragic.” More positively, it also means the other person’s onset starts later. “Well, that’s exactly what we want a drug to do.”

Human data has played a major role, he pointed out. With thousands of HD-affected people participating, researchers have been able to examine their genetic composition, involving not just their Huntington’s gene, “but their entire genome, to do what’s called a Genome Wide Association Study, or GWAS, and figure out what it is that’s different about individuals that causes one person’s Huntington’s to start earlier than another,” Dr. Pacifici explained.

In his presentation titled “Medication of Huntington’s disease by genetic variations,” Dr. Lee reported how the large research team seeking modifier genes has narrowed its search to chromosomes 3, 8, and 15. (Located in all of a human’s cells, the 46 chromosomes are long, twined strands of DNA containing a person’s entire genetic heritage.) According to Dr. Lee, chromosome 15 has both a “bad” and “good” modifier, with a six-year difference in onset between individuals having one versus the other.

“If we can identify that [good] gene and figure out how it’s doing that, then what we have is a very specific set of instructions for drug hunters to make a compound that does that same thing,” Dr. Pacifici said.

Jong-Min Lee, Ph.D. (photo by Gene Veritas)

‘Cheating a little bit’ with biomarkers

The second example involves cerebrospinal fluid (CSF), the liquid that bathes the brain and circulates up and down the spine. Researchers have been searching for HD-related biomarkers in samples of CSF taken from volunteers afflicted with the disease as well as so-called premanifest people, individuals who (like me) carry the gene but have yet to show classic, easily notable symptoms such as involuntary movements (chorea and other types).

Dr. Pacifici defined biomarkers as “a way of cheating a little bit” to get signals without waiting for the more time-consuming and more expensive later phases of a clinical trial.

The human brain can only be studied directly only after a person has died, as pointed out in a talk on CSF by Ed Wild, M.D., Ph.D., of the University College of London. Imaging methods such as MRI are helpful but very limited. So scientists are putting ever greater emphasis on finding signals in the CSF such as mutant huntingtin protein and other biomarkers.

CSF provides a “snapshot of what’s going on in the human brain,” Dr. Pacifici observed, adding that it might indicate in a clinical trial whether a huntingtin-lowering drug is having the desired effect.

Clinical trial administrators would still need to wait many months to get meaningful observations about actual effects on symptoms, but seeing what the drug does at the molecular level is a key first step.

“In other words, we don’t want to give the drug [. . .] and hope that after three years of waiting that we’re going to have an effect,” he said. “We want to know right away that that drug was doing the job that it was charged to do, in this case lowering huntingtin levels.”

A CSF study

Describing the analysis of CSF from HD patients in a research study of twelve individuals that he helped direct, Dr. Wild observed that the closer a premanifest individual was to probable onset, the higher the level of mutant huntingtin found in the CSF. Similarly, among affected individuals higher levels of the mutant protein correlated with worse symptoms.

Dr. Wild and other scientists are still striving to determine the specific origin of the mutant huntingtin found in the CSF. At this point they hypothesize that it comes from neurons, a specific type of brain cell.

Scientists aim to improve CSF collection efforts and obtain a clearer understanding of what occurs in the CSF through a new, CHDI-funded project called HDClarity. The initial research sites are at University College of London, the University of British Columbia, and the University of Ulm, Germany.

You can watch Dr. Wild’s presentation in the video below.

Biomarkers and Biological Insights from Huntington's Disease Patient Cerebrospinal Fluid from Gene Veritas on Vimeo.

The rise of clinical trials

The need for clinical trial volunteers will increase dramatically as the number of trials grows rapidly.

With a total of nine active trials, 2014 had an “unprecedented amount of activity in clinical trials in Huntington’s disease,” Ray Dorsey, M.D., a professor of medicine at the University of Rochester and the president of the Huntington Study Group, stated in an overview of recent HD trials.

These trials included the two largest-ever regarding HD: a study of coenzyme Q10 with 609 participants and a study of creatine with 553 participants. Both were halted because of lack of efficacy, but helped scientists understand the need for better evaluation of substances before taking them into a trial, Dr. Dorsey noted.

Last year brought one of the few successes in HD clinical trial history: the highly favorable results of Auspex Pharmaceuticals’ testing of its compound SD-809, which reduces chorea substantially and with fewer and milder side effects than its predecessor drug, tetrabenazine.

Presenting a chart of clinical trial trends, Dr. Dorsey demonstrated that the number of HD trials is growing exponentially: from four trials in 1999-2002 to 28 trials in the period 2011-2014.

“I think we’re poised for success,” he concluded.

10th Annual HD Therapeutics Conference participants watch a presentation (photo by Gene Veritas)

Assessing the potential of gene-silencing

In reviewing the clinical trial outlook for 2015, CHDI’s consulting medical director, Bernhard Landwehrmeyer, M.D., Ph.D., noted the continued upward trend, with six active trials.

Dr. Landwehrmeyer described the plans for a Phase I gene-silencing clinical trial by Isis Pharmaceuticals, Inc., and Roche. This approach seeks to attack the causes of the disease at its roots (click here to read more).

Isis’s senior vice president for research, Frank Bennett, Ph.D., stated in his conference presentation that the trial would begin by the end of the second quarter, but Dr. Landwehrmeyer predicted it would start later in the year. It is only the very first step in gene-silencing treatments for HD, he stressed.

Nevertheless, he observed that many other companies and labs are working on their own versions of gene-silencing treatments for HD. The chart he displayed showed 14 other entities in addition to Roche and Isis.

“It’s important that we have such a rich toolbox in attempts to make gene-silencing a therapeutic reality,” Dr. Landwehrmeyer said.

He noted that the Isis/Roche trial is unusual because it must include symptomatic patients, who will receive the gene-silencing drug via a spinal tap. Typically a Phase I trial accepts only healthy volunteers because it is testing for safety and tolerability, not for efficacy.

The trial will take place at HD centers in England, Canada, and Germany that have in-patient intensive care monitoring facilities, he noted.

Dr. Landwehrmeyer said it was important to set realistic expectations for the HD community, which anxiously awaits good news about gene-silencing because of its potential to significantly impact the disease.

“You are NOT missing the boat, if you do not participate in the Isis study,” he said, referring to HD-affected individuals. Establishing safe and effective gene-silencing therapies for HD will still take “decades.”

Once trials prove them to be safe and effective, these drugs can reach the market and become available to all HD families.

Bernhard Landwehrmeyer, M.D., Ph.D. (photo by Gene Veritas)

Big challenges remain

Dr. Landwehrmeyer also commented on the other trials taking place this year: Pride-HD (to test pridopidine); APACHE and Amaryllis (to test “Viagra for the brain”); LEGATO-HD (to test laquinimod); and a forthcoming trial in deep brain stimulation.

In all, he noted, at least 1,500 HD patients are expected to take part in clinical trials this year.

“That’s on the one hand fantastic,” he said. “But timely recruitment into these studies has become an issue.”

Some HD study centers are underutilized, while others are overloaded, he noted. The number of trial participants is further restricted by inclusion/exclusion criteria (for example, the particular disease stage of the patient). Pharmaceutical companies should enhance a “culture of cooperation” regarding trials, he said, and regional and national patient advocacy organizations need to activate their networks.

Enroll-HD, the global platform, research project, and family registry aimed at facilitating clinical trials and the discovery of treatments, recently reached a milestone with its 5,000^th registrant, but needs to grow to as many as 30,000, Dr. Landwehrmeyer observed.

Hoping for an end to conferences – and HD

The 10^th Annual HD Therapeutics Conference had numerous other compelling presentations on the search for treatments. Click here to visit my video album, where you can view many of the presentations.

The conference also featured some 90 posters detailing cutting-edge HD research projects.

Conference attendees view posters of Huntington's disease research projects (photo by Gene Veritas)

“Obviously we’re a time-motivated organization, and we know patients are waiting,” Dr. Pacifici said. “So the fact that it’s taken us ten years to get to this stage is not necessarily something to celebrate. That said, I think we should pay homage to the progress that’s been made over that period of time.”

Dr. Pacifici observed that with well-designed clinical trials, “it’s really an exciting time” in the quest for treatments.

He said that he was struck by the courage and collaborative spirit of the community, from academia to the private sector to the families. He also thanked HD families and their supporters for their participation in research studies, clinical trials, and other activities.

“This isn’t a competition,” he declared. “This is an opportunity for all of us to enable each other, which I don’t take for granted, because one of the potential downsides of getting to the endgame – which we are – is that’s when people start to be a little more secretive and a little bit more protective. We saw here time and again even multinational pharmaceutical and biotech companies standing up at our conference and presenting new, unpublished findings so that everybody could benefit from them.”

Along the way, failures will occur, because drug discovery is a very inefficient process, he emphasized. (Only one in ten clinical trials results in a marketable drug.)

“That’s frustrating,” he recognized. “Don’t be disheartened. Know that we have a large and deep portfolio [and] that we’re going to learn from each one of these failures. I think, and I have every confidence, that we’re going to start getting real positive signals that then we can build on. And that’s when the fun starts.

“I hope we’re sitting here together again next year for the eleventh conference, but I also hope we’re not sitting down here for too many more. And I mean that in a positive way.”

* * *

For additional coverage of the conference, visit HDBuzz.net.

(Disclosure: I hold a small number of shares of stock in Isis Pharmaceuticals, Inc.)

‘Predicting’ Huntington’s disease in the heartland

To develop treatments for a disease, researchers and physicians first need to understand how its symptoms evolve and how they affect people’s lives.

In early August, I traveled to the University of Iowa in Iowa City to donate blood, urine, and saliva samples, undergo a motor coordination exam and brain MRI scan, and perform a battery of cognitive and mood tests for the long-term research study Neurobiological Predictors of Huntington’s Disease, best known as PREDICT-HD, one of the largest public-private research projects in the history of the quest to defeat the disease.

My biological samples will become part of a bio-repository at the National Institute of Neurological Disorders and Stroke (NINDS), a division of the National Institutes of Health (NIH) located just outside Washington, D.C. Researchers from around the world can apply for access to these materials.

In studying gene-positive, asymptomatic people like me, the scores of researchers working at the University of Iowa, 26 other PREDICT centers in the U.S. and abroad, and many other institutions can try to analyze how the early symptoms of HD develop.

They are also seeking to identify HD “biomarkers” in the blood, cerebral spinal fluid (CSF), and brains of the study participants, who include formerly at-risk individuals who tested negative for HD. These individuals serve as a control, or comparison, group to ascertain which changes in the gene-positive people are specifically caused by HD.

Gene Veritas in preparation for PREDICT-HD MRI scan (photo by Sarah Petitt)

With biomarkers and other study data, researchers can effectively measure the effectiveness of potential treatments in upcoming clinical trials.

Patients: study us!

The lead scientist and administrator of the multi-million-dollar PREDICT study is Jane Paulsen, Ph.D., the co-director of the University of Iowa Huntington’s Disease Society of America Center of Excellence and Professor of Psychiatry, Neurology, Psychology, and Neuroscience. From 1991-96, she was a postdoctoral neuropsychology fellow at the University of California, San Diego (UCSD), where she directed the HD clinical research program and came into close contact with the local HD community.

“The desire to move towards earlier detection and identification was really brought forth at UCSD from the families,” Dr. Paulsen recalled in an August 6 interview. Such families, she noted, told her: “‘You know, I’ve been dealing with this for years, and it isn’t validated by the professional community. I don’t have a diagnosis. A lot of people just think I’m exaggerating.’

“So just that sense of so many people who are at risk, who might be having subtle symptoms. When we would see them, we could detect maybe cognitive or certainly emotional changes that might occur. There’s a lot of stages that occur before you get the motor signs and diagnosis.

“So the whole PREDICT project was sparked by families in San Diego saying, ‘I’ve seen this forever, and we need to detect it sooner, before I lose my job or blow up at my kids or I don’t take care of my home responsibilities the same or my friends don’t understand me the same or my family doesn’t understand me the same. If we could move it back and better understand it, then we could maintain all those additional components of my life.’ So that was really the motivating factor – trying to get people to look at it this presymptomatically, before that diagnosis.”

The decision to start PREDICT occurred in 1998 at an executive meeting of the physician-researcher collective known as the Huntington Study Group, of which Dr. Paulsen was a founding member. PREDICT formally began in 2001.

With its focus on the asymptomatic, PREDICT could help identify and test preventative treatments – the “holy grail” of HD research.

“Eventually, when they have a treatment, we want to intervene as soon as possible, because the sooner we intervene in the brain, the less tissue loss, the less dysfunction, the less toxicity has occurred,” Dr. Paulsen explained. “Even if we slow it 15 percent, which is all that they’ve done in other brain diseases, since HD lasts so many years – we’re thinking 40 years now – 15 percent could be many years where you could maintain a higher level of functioning.”

You can watch the entire interview with Dr. Paulsen in the video below.

Maximizing research

PREDICT seeks to “maximize” HD research, Dr. Paulsen said. “We work with anybody who wants to work on a particular aspect of the disease.”

As the PREDICT flagship, the University of Iowa has collaborated with its sister PREDICT centers and also partners and subcontractors at other academic institutions in the U.S. and abroad. The partners focus on cognitive testing, brain imaging, and motor studies. They include leading universities such as Johns Hopkins University, Brown University, and the Massachusetts Institute of Technology. On protein studies, PREDICT collaborates with Caprion, a private firm.

PREDICT had as many as 33 centers but currently has 27 active sites. Worldwide some 1,500 individuals, including 1,200 gene-positive, have participated in PREDICT. The study seeks to follow 1,000 individuals on a regular basis.

Stimulated largely by PREDICT, Iowa alone has produced a critical mass of innovative HD research in what Dr. Paulsen described as an “explosion” in knowledge about the disease over the past decade.

Among the 20-plus projects at Iowa over the past decade, Dr. Paulsen described research on clinical markers of the disease; biomarkers; proteomics (the study of HD-associated proteins); bone mass and metabolism; MRI scans; PET scans; full genome-wide scans (looking at all the genes in study participants); comparisons of symptoms among people with the same level of genetic mutation; the impact of discrimination and stigmatization on gene-positive people; and the possibility that HD might have vascular, immunological, or inflammatory components.

PREDICT researchers and their collaborators have published numerous scientific articles on presymptomatic HD and other aspects of the disease. These include studies seeking to refine cognitive testing; measure the relationship between estimated disease onset and the likelihood of the use of antidepressants; detect brain cell loss as an early HD imaging biomarker; and gauge the loss of perception and processing time in individuals.

Under Dr. Paulsen’s leadership, Iowa has also taken a key role in the study of juvenile Huntington’s disease, a form of the condition often given little attention by researchers because it accounts for just 10 percent of all HD cases.

Crunching the data

To help form research questions, search for useful biomarkers among the large amounts of data collected by PREDICT-HD, and help plan their use in clinical trials, the project enlists the skills of biostatistician Jeffrey Long, Ph.D., a professor of psychiatry.

“I mainly focus in tracking progression over time,” said Dr. Long, the author of a textbook on the open-source computer program known as R, used widely by statisticians and in the PREDICT research. “We try to make use of every piece of data because we are appreciative of the time you all devoted to the study and want to make sure that we maximize the relevant information for the community.”

Gene Veritas (left) interviewing Dr. Jeffrey Long (photo by Sean Thompson)

The seven-member bio-statistical team led by Dr. Long analyzes the different kinds of data collected individually and in combination. The team also helps draw comparisons between data from gene-positive and gene-negative individuals to account for factors such as cognitive loss due to natural aging.

Additionally, the scientists seek to understand the key relationship between the level of genetic mutation and the age of onset and severity of the disease. They have helped identify one key imaging biomarker: the diminishing size of the brain region known as the putamen before disease onset. They have also noted an abundance of a particular kind of protein in the bloodstream of gene-positive individuals.

A special connection

To coordinate visits by PREDICT participants and administer questionnaires and cognitive testing, the project employs several study coordinators, including research associate Stephen Cross.

“I’ve fallen in love with the population,” said Cross. “They talk about the ‘HD bug.’ I’ve got the bug. There’s something unique about this population. I think it’s the family aspect of it. I would feel like I was abandoning the cause to work with another group.”

With PREDICT since 2008, Cross currently has a caseload of some 80 individuals and their families.

PREDICT-HD study coordinator Stephen Cross (left) conversing with Gene Veritas (photo by Sarah Petitt)

“All of them have their lives changed by the genetic testing, regardless of the results, whether it’s positive or negative,” he observed.

He said that, in the case of gene-positive individuals, especially those from families who can trace the disease back a number of generations, “I think it changes their souls, when you know what’s coming in the family, when it’s in yourself. There’s some kind of interaction in this triad of symptoms – the movement, the psychiatric and the cognitive. I think you’re special because of this disease. I feel a spiritual connection with my participants.”

Brain and body scans

“We have many imaging studies,” said Dr. Paulsen. “We’re looking at the shape changes in the brain.”

Imaging provides a picture of HD without the “need to poke around in the brain,” Dr. Paulsen noted.

 “We already have a very good imaging marker,” she continued. “We can measure the volume of the part that’s particularly sensitive to Huntington’s disease, the striata or the basal ganglia. We can see that it changes a percentage every year of the disease. Even as far back as ten, 15 years prior to diagnosis. But we want to get are even better imaging markers, maybe ones that are earlier or maybe one that gives us a more robust signal. So that’s why we have a lot of projects right now that are really trying to challenge what we can learn from brain imaging.”

Gene Veritas (above) walks through a metal detector in preparation for a PREDICT-HD MRI scan performed after MRI radiology technician Marla Kleingartner (below) secures his head to prevent movement during the scan (photos by Sarah Petitt).

In addition to markers, imaging has revealed new information about the extent of the disease, Dr. Paulsen added. Scientists long thought HD affected only the basal ganglia, the area of the brain responsible for motor function.

“The imaging data that’s been published over the last decade shows that it’s much more widespread in the brain,” she said.

With the lack so far of significant HD biomarkers in the blood and urine, PREDICT is now starting to study CSF collected from a number of its previous and current participants by way of a spinal tap.

(I could not donate CSF because a previous lower back injury made the procedure too risky for me.)

A full-body scan

As a registered nurse, Nancy Downing, Ph.D., takes a holistic approach to HD-affected individuals, always seeking to improve their quality of life.

Several years ago, an NIH seminar on genetics helped solidify Dr. Downing’s interest in HD, she said. Today she seeks to integrate genetics and efforts to improve patients’ quality of life. As a PREDICT researcher, she has especially focused on the effects of diet and exercise and the way in which lifestyle affects the expression of genes.

Just two months ago she helped complete a pioneering twelve-month study in which a group of PREDICT participants underwent dual x-ray absorptiometry, a scan that reveals the composition of a person’s body mass (lean, fat, and bone). This same machine is used to detect osteoporosis.

Nancy Downing, Ph.D., RN, SANE-A (photo courtesy of HDSA Center of Excellence at the University of Iowa)

Dr. Downing hopes to triangulate the data from this study to help understand what HD does to areas of the body other than the brain such as muscle tissue. Evidence already suggests that gene-positive individuals have a shortage of branched-chain amino acids, necessary for muscle building and repair, she said.

Dr. Downing’s work supports the growing notion that HD must be seen as a disease of the body and not just the brain.

Preparing for clinical trials

PREDICT can have an impact on clinical trials and the approach treatments might take, Dr. Paulsen said.

“It’s kind of a when, where, how question,” she said. “I don’t think any of those questions is fully answered, so we have more work to do. But we have answers to those questions that we didn’t have before.

“We didn’t know that there was a when, where, how. We thought that once they get a diagnosis, we’re going to try to treat them with something that we’ve learned from other neurodegenerative diseases. I think in many ways Huntington’s has opened up that box and made it much larger. It’s a very exciting time. And I think it will continue. We’re not even close to the end of the possibilities on where we intervene, (and on) the changes of Huntington’s disease.”

PREDICT, with its unique database of long-term data on presymptomatic individuals, could potentially furnish important data for clinical trials, she added.

“We have this entire cohort,” she explained. “We know exactly how much change they have over time. If we do an intervention, we will be able to determine how much change has occurred. No other study can do that, because if you recruit someone new, you don’t know that individual’s trajectory. We have each individual’s trajectory. We know what type of progression they have. If there was a treatment today, this is the group we should put it in, because we tell exactly what’s going on with that person.”

A potential key treatment

In collaboration with PREDICT and other HD projects at Iowa, the lab of Beverly Davidson, Ph.D., is engaged in research aiming for a clinical trial to test a gene-silencing drug that could at least partially halt HD at its root cause.

This approach would involve the use of RNA interference (RNAi) molecules permanently introduced into the brain via the injection of a virus by a neurosurgeon.

Similar to two separate gene-silencing clinical trials planned by Isis Pharmaceuticals, Inc., and Roche and a team involving Medtronic and the non-profit CHDI Foundation, Inc., the potential Davidson lab therapy aims to reduce the production of harmful huntingtin protein by interrupting the natural translation of the gene into protein.

In HD mouse testing, the lab has demonstrated that RNAi reduces the toxicity of the bad gene in the brain and alleviates symptoms, Dr. Davidson said.

She explained that RNAi is currently under study in a clinical trial for Leber congenital amaurosis, a retinal disorder that leads to blindness in children.

“They put this into the eyes of these children, and the children are showing remarkable, remarkable results,” Dr. Davidson said.

Two of the Leber pioneers, Katherine High, M.D., and Jean Bennet,M.D., Ph.D., are “collaborating with us to develop the gene therapy vectors for Huntington’s disease,” Dr. Davidson noted.

Dr. Davidson said her team hopes to start a clinical trial within the next two years. “That might be aggressive, but we’ve been putting in a lot of effort in the background in the last year or so,” she said.

To learn more about this project watch my interview with Dr. Davidson in the video below.

PREDICT’s ending, gratitude to funders

Although currently operating at full steam, at least in its current form PREDICT is scheduled to end on July 1, 2014.

From 2001-2013, PREDICT received a total of $46.8 million in National Institute of Neurological Disorders and Stroke (NINDS) funding. Additional support has come from the National Human Genome Research Institute and the National Institute of Mental Health. The CHDI Foundation has also infused $15.5 million into the project and is providing further assistance.

In the last five years of the study, PREDICT received $5.6 million annually in federal funds from NINDS. The 2013-2014 fiscal year costs are being covered from funds incurred from previous years.

“I was told that NINDS won’t consider any more budgets over $1 million,” said Dr. Paulsen, noting the high cost of this kind of research. She said Iowa would be unable to continue the PREDICT study in its current form with so little money. Just bringing patients to Iowa is a major expense.

NINDS has experienced cuts in recent years. For fiscal year 2013, the federal government cut five percent of the NINDS budget as part of the $85 billion in overall spending cuts determined by Congress, including the sequestration provisions legislated in 2011.

In addition, CHDI is now shifting its priorities to implementing a new worldwide HD patient study and database known as Enroll-HD.

Nevertheless, Dr. Paulsen recognized the significance of NINDS funding, described by one observer as the largest HD project ever funded by the agency.

“I understand NINDS,” Dr. Paulsen said. “They’ve been cut every year. We’ve been fortunate to receive funding from them for years, and CHDI has supplemented us. They had us expand and train some sites to expand. They have supplemented us when we ran into obstacles. CHDI has been very forthcoming in assisting. So they’re just always there in the wings saying, ‘What can we do to make this go better?’ They really want to push things forward.”

Assessing PREDICT’s impact

Asked to reflect on the ultimate causes of PREDICT’s expected termination, Dr. Paulsen stated that she’s “not sure I have the right answer. I have my opinion. There are centers that have followed research projects for decades.”

The federal government has supported such ongoing centers for AIDS, Alzheimer’s, Parkinson’s, and alcoholism, she noted.

However, once again, HD’s status as a rare disease might be leading officials to treat it as insignificant, Dr. Paulsen indicated. Others might have misunderstood PREDICT to have failed to innovate.

She rebuts those notions.

“The output of this project has been far greater than many other of the ongoing centers,” she observed, adding that HD research has contributed significantly to the study of other conditions. “It’s definitely been a project that has morphed and kept up and pushed the envelope. It would be nice to be funded like other centers that just are kind of automatically rolled over.

“We have to be protective of our resources, but the amount we are learning has just become exponential. It has grown so much and it isn’t stopping. Most of the projects I’m talking about are brand new. They’re just starting to look at CSF, at new imaging markers, at trajectories.”

Despite these setbacks, Dr. Paulsen said that HD research would continue at Iowa. New grant applications are already in the works, she said.

The Iowa HDSA Center of Excellence will also continue its activities.

My future in PREDICT

In line with PREDICT’s goal of tracking patients over time, the Iowa team has already notified me that I should return next year for a follow-up examination, before the July 1, 2014, end date.

Ideally, I should also make a third visit at a later date for the researchers to have sufficient data points. The uncertain budgetary situation has cast doubt on that possibility.

Regardless, I feel privileged to have contributed as an HD-positive individual to the quest for treatments, and I am thankful to the numerous researchers and support staff of PREDICT-HD and the public and for the private funding that has made this initiative possible.

(Next time: advocacy meets science and medicine in Iowa and beyond.)