A key new ally in the search for Huntington’s disease treatments

With the new partnership between Roche and Isis Pharmaceuticals, Inc., reported here on April 11, the search for Huntington’s disease treatments has gained an accomplished and ambitious ally in the person of Luca Santarelli, M.D., Ph.D.

Dr. Santarelli, the 44-year-old head of neuroscience and small molecule research at Roche’s world headquarters in Basel, Switzerland, will oversee the Roche-Isis effort to bring Isis’s proposed gene-therapy drug to a long-awaited crucial clinical trial, tentatively scheduled to start in the first half of 2014.

A native of Italy, Dr. Santarelli in the early 2000s made an astounding discovery about Prozac-type antidepressants while conducting postdoctoral research at Columbia University in New York City: these drugs actually led to neurogenesis, the birth of new neurons in the brains of adults.

With these findings, Dr. Santarelli joined Nobel laureate Dr. Eric Kandel, Dr. Rene Hen of Columbia, and Dr. Fred Gage of the Salk Institute for Biological Studies in San Diego to found a company, Brain Cells, Inc., that focused on the development of novel antidepressants for stimulating neurogenesis.

In 2005, Dr. Santarelli joined Roche. He quickly rose in the company ranks and now oversees efforts to design drugs for brain disorders and related conditions, including schizophrenia, depression, Alzheimer’s disease, multiple sclerosis, spinal muscular atrophy, and neurodevelopmental disorders such as autism and Down syndrome.

Nature’s Trojan horses

Now, turning their attention to HD, Santarelli and Roche researchers will collaborate with Isis to speed progress towards the clinical trial, infusing $30 million into the project.

They also will seek ways to make the potential Isis drug easier for trial participants and eventual patients to absorb. Instead of Isis’s potentially riskier and certainly less comfortable method of implanting a quarter-sized port near the rib cage connected to a catheter running to the area of the spinal cord, Roche aims to create a drug that patients could take through an intravenous or subcutaneous (under the skin) injection. (It’s still too early to tell where in the body patients would receive such a potential subcutaneous injection.)

To design this kind of drug, Roche will use a so-called “brain shuttle,” a new approach to transporting drugs past the highly impermeable blood-brain barrier, which protects the brain from foreign objects.

The blood-brain barrier also makes it difficult for so-called large molecule drugs to enter the organ and thus has presented researchers with a major hurdle to treating brain disorders and diseases.

Dr. Santarelli, in a phone interview on April 22, was asked to explain the brain shuttle in everyday terms.

“It works by hijacking a biological system that is normally used to shuttle proteins into the brain,” he told me. “It uses cellular receptors outside the blood brain barrier and uses them as Trojan horses to take in a cargo.”

Dr. Luca Santarelli (photo courtesy of Roche)

The cargo could include an antisense oligonucleotide, or ASO, the specially designed piece of artificial DNA made by Isis that, in mice experiments, has reduced the amount of the harmful huntingtin protein in brain cells and produced a “Huntington’s holiday,” a disappearance of the symptoms.

“A cargo can be an ASO,” Dr. Santarelli continued. “It could also be a peptide or an antibody. Receptors are on the outside (of the blood-brain barrier), but they also move to the inside. They are built by nature to allow certain large molecules (to move in).”

Explaining the concept

No brain shuttle drug yet exists. I was eager to know exactly what kind of shuttle Roche might have in mind and how it could work with the ASOs.

However, because of the trade secrets involved in private drug research, Dr. Santarelli declined to comment.

Nevertheless, he emphasized that the brain shuttles are “built by nature to allow the transfer of large proteins inside the brain.” Different shuttles have different capacities, he added, and they work in a “controlled fashion.”

“The concept of proteins that shuttle large molecules has been known for a while,” he said, referring to the decade-plus research on the phenomenon.

Dr. Santarelli cited the example of the shuttle known as transferrin.

“We know that transferrin works in this way,” he said. “Transferrin is a protein that carries around iron in the bloodstream. Iron doesn’t go around freely. It’s absorbed and transferred around to the organs. It (transferrin) binds with iron – iron gets released into the brain.”

Advantages of the brain shuttle

By carrying an ASO into the brain in this revolutionary manner and avoiding the discomfort of a lumbar (lower-back) puncture or other long-term invasive approach, the brain shuttle approach helps drug discovery in two key ways.

First, it allows researchers to include people in clinical trials who previously were not eligible – namely, people genetically at risk for a disease but without symptoms. In terms of ethics and comfort, it is difficult to justify their participation because of the risk posed by invasive procedures.

With the brain shuttle, however, discomfort is reduced. So is the ethical barrier, because the injury risk diminishes.

Secondly, by including presymptomatic people in drug studies, researchers can measure how a drug affects a patient before the disease develops, thus providing clues about how to stop the disease from ever occurring.

Only a few years ago, this kind of approach to neurological drug research seemed futuristic. The lack of opportunities to participate in clinical trials and the absence of a strategy to prevent the disease in asymptomatic people have proved especially frustrating for the HD community, where people like me await in great fear the onset of a disease foretold by genetics.

A unique Alzheimer’s trial: intervening early

With Isis, Dr. Santarelli and Roche are working to raise the hope of preventing asymptomatic gene carriers from ever experiencing onset.

Roche is especially well-positioned because, as Dr. Santarelli pointed out, it focuses on both drug development and disease diagnostics.

Roche’s “strategic objective” is to intervene “as early as possible” in the course of the disease, he emphasized.

“As an organization, we’ve done this in Alzheimer’s,” he explained.

In developing its proposed Alzheimer’s drug, now under study in a clinical trial involving 800 patients, Roche has taken the unique step of including individuals who have not yet developed dementia, but have merely mild cognitive impairment, Dr. Santarelli said. (Click here for further background.)

In the trial Roche is using molecular testing to diagnose and select trial subjects at risk for Alzheimer’s. This is done by performing a lumbar puncture to obtain a sample of cerebral spinal fluid (CSF) to check the presence of amyloid, the substance that forms plaques in the brain of Alzheimer’s patients and is considered one of the causes of the disease.

If successful, the Roche drug will not only clear plaques from the brains of the Alzheimer’s patients but also delay (or stop) the progression of the disease, Dr. Santarelli said.

The diagnostic technique used in the trial to measure CSF amyloid is experimental and has yet to reach the market, Dr. Santarelli noted.

He stressed that the Roche approach involves both the more traditional clinical (observational) measurement of the patients’ symptoms and, with this new measurement technique, a molecular measurement.

Roche's “culture of combining diagnostics and therapeutics” will definitely provide useful for the development of HD drugs, Dr. Santarelli observed.

A number of other HD research efforts also focus on the search for molecular measurements.

Patient involvement

Because of the highly experimental nature of the brain shuttle and the newness of Roche’s neurological diagnostics, Dr. Santarelli could not forecast when these approaches will bear fruit in HD research.

“We have to go through all the experimentation,” he said of the partnership with Isis.

Whatever the timeline, Roche will depend on collaboration with the HD community, as it has with advocates for other diseases.

“You guys are playing an extremely important role for lowering barriers to making progress in this area,” he said. “I feel personally honored that I can make a contribution in this area.”

Designing the best drug possible to defeat Huntington’s disease

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

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

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

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

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

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

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

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

  

Fine-tuning, tailoring, and twiddling

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Patient-friendly delivery

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

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

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

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

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

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

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

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

Getting into the brain

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

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

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

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

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

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

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

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

A ‘Huntington’s holiday’

The most stunning test results involved the amelioration of symptoms.

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

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

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

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

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

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

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

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

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

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

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

Measuring the impact in people

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

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

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

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

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

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

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

Light in the tunnel

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

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

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

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

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

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

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

Lifting Huntington’s families’ spirits with the promise of clinical trials

Perhaps nothing lifts the spirits of struggling Huntington’s disease families more than news about research breakthroughs.

With people emitting oohs and ahs about some of the key developments, you could feel the excitement in the room Monday evening, September 24, as Jody Corey-Bloom, M.D., Ph.D., presented her annual research update to the support group of the San Diego Chapter of the Huntington’s Disease Society of America (HDSA).

The director of the HDSA Center of Excellence for Family Services and Research at the University of California, San Diego (UC San Diego), Dr. Corey-Bloom kicked off the update with the hottest topic in the HD research world: gene silencing techniques aimed at attacking the disease at its roots.

“This is a big thing,” Dr. Corey-Bloom stated. “There are actually two methods to accomplish this that are under way in research labs around the world…. We want to switch off the gene that is responsible for Huntington’s disease. A lot of people feel very good about these techniques.”

Before a room packed with some 50 support group participants, Dr. Corey-Bloom proceeded to outline the efforts to set up clinical trials to test RNA interference (click here to read more) and antisense oligonucleotides (ASO) (click here to read more) as ways to block the negative effects of the HD gene, which produces a harmful protein.

“If we can get rid of this harmful protein, there’s a good chance that we could slow down the disease or even prevent it,” Dr. Corey-Bloom explained.

Dr. Jody Corey-Bloom at a 2010 HD research meeting (photo by Gene Veritas)

A trial in 12 months?

“It’s likely that we’ll see both approaches being tried,” Dr. Corey-Bloom said, noting, that, given the current state of the science, it appears that the ASO approach will enter a trial first.

Dr. Donald Cleveland of UCSD and Isis Pharmaceuticals, Inc., of Carlsbad, CA are nearly “ready to go” with a clinical trial, perhaps as soon as within 12 months, she observed.

“The critical thing to say here is that we really are edging closer to human trials,” Dr. Corey-Bloom emphasized.

The trial site has not yet been determined.

Dr. Cleveland, UCSD’s Ludwig Institute, and Isis will be honored at HDSA-San Diego’s 12^th Annual Celebration of Hope Gala on November 16, 2012.

In the coming weeks, I will report in detail on the UC San Diego/Isis project, which is mainly underwritten by the CHDI Foundation, Inc., the multi-million-dollar, non-profit biomedical research foundation dedicated exclusively to accelerating Huntington’s drug discovery and development.

You can watch Dr. Corey-Bloom’s presentation in the video below.

The shock of HD’s reality

Having tested positive for HD in 1999 and watched my mother succumb to the disease in 2006, I was thrilled to hear the news about the Isis ASO trial.

I have tracked the progress of the project since early 2008, shortly after the start of the CHDI-Isis collaboration (click here to read more).

Isis had first estimated that a clinical trial could start in late 2010. As with many scientific endeavors, delays have occurred. Now that a trial could realistically begin next year, I can once again fantasize about living free of this scourge that robbed my beloved mother of her ability to walk, talk, eat, and care for herself, leaving her a mere shadow of herself.

The support group meeting proved especially poignant for me because I had not attended for a number of months. After a summer break from my usual intense focus on HD, I once again confronted the reality of my own future in the faces of the HD-affected individuals I saw at the meeting.

Seeing these disabled individuals shocked me into renewing the fight to save them – and myself.

At 52, I am now at mother’s age of onset. Once again, I felt extremely lucky to have avoided the noticeable, classic symptoms of HD.

Imagining a healthy future

I have attended Dr. Corey-Bloom’s updates for about ten years. Each time, she manages to provide clearer and more comprehensive information.

Squeezing literally dozens of research developments into an hour-long talk and making it understandable for a general audience is no small challenge. As I told her afterwards, “You just get better every year!”

This year’s update especially served like a salve to calm my worries, which had heightened considerably after hugging one HD-affected friend who seemed to have declined since I last saw her a few months ago.

As Dr. Corey-Bloom spoke, I imagined this HD sister becoming healthy again and happily growing old with her family.

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.)