HDSA’s renewed commitment to critical research

After a budgetary crisis that practically eliminated support to HD scientists in recent years, the Huntington’s Disease Society of America (HDSA) has committed itself to reestablishing a program of research projects critical for developing effective treatments.

In a September 28 e-mail message to “HDSA friends,” HDSA CEO Louise Vetter announced the hiring of George Yohrling, Ph.D., to fill the new position of Director of Medical & Scientific Affairs.

“In the past we have relied upon the volunteer support and consultation of physicians and scientists,” Vetter explained in an interview in San Diego on November 16. “We will continue to do so. But based on what the pace of HD research is right now and our vision to have a new research program, we felt it was the right time to bring that expertise in-house.”

Dr. Yohrling, a molecular neuroscientist, has worked in the HD field since 2000.

“His first job was with an HDSA Coalition for the Cure lab,” Vetter said. “He was funded with an HDSA grant, and he has continued to stay in the field.... He has real expertise in HD, which is incredibly important. His primary task is to launch a new research program for the organization.”

The hire marks the first step in fulfilling a series of goals outlined in HDSA’s first-ever strategic plan, formulated after broad consultation with the HD community in 2011 and 2012, and launched by Vetter at the annual HDSA convention last June (click here to read a report on the drafting of the plan).

In response to recent criticisms of HDSA because of the drastic decline in research support (click here to read more), Vetter stated that HDSA is working “to have the most impact for the most people and help set the course for the best care and the best treatments as soon as possible.”

(Watch the entirety of my interview with Vetter in the video below.)

Avoiding repetition

In crafting the new research program, HDSA planners took into account the organization’s limited budget (about $8.5 million annually) and strived to avoid duplicating efforts by other HD initiatives focused strictly on research, Vetter added.

Those initiatives include the CHDI Foundation, Inc., which spends tens of millions of dollars annually, and the Hereditary Disease Foundation (HDF). Unlike HDSA, they do not offer support groups, care centers, or other forms of patient outreach.

Both Vetter and Dr. Yohrling emphasized that the new research program will focus on HD research in humans and human cells. This contrasts sharply with – but also necessarily complements – the research conducted on animals.

Focusing on humans

“We’re calling it ‘Human HD Biology Project,’” Dr. Yohrling said in a November 26 interview. “All of the observations will be from human HD patients, and not from a worm or mouse or fly. There’ll be no arguing about the physiological relevance of the data we will acquire.”

Dr. Yorhling explained that the project will function like a post-doctoral or clinical fellowship program. Young scientists will partner with the directors of HDSA’s 21 Centers of Excellence for Family Services and Research, which see patients and other HD family members on a regular basis. It replaces the Coalition for the Cure grant program, which ceased to exist with the onset of the budget crisis.

Dr. George Yohrling (CHDI photo)

The new researchers will focus on tasks such as the search for human biomarkers – specific signs of the disease within bodily fluids or tissues or the brain, for example – that will become crucial for measuring the effects of potential remedies.

“These are studies, not clinical trials, but their outcome could and should help support, drive, and steer clinical trials,” Dr. Yohrling explained, adding that he is currently recruiting HD specialists to serve on the program’s advisory committee, which will review the applications from researchers.

Grants will be relatively modest, Dr. Yorhling indicated. “These won’t be $250,000 jobs,” he said. However, because of the clear emphasis on non-redundancy, “hopefully we’ll get a big bang for our buck,” he added.

HDSA has already raised funds to kick off the project, Dr. Yorhling said, although both he and CEO Vetter recognized the need to increase fundraising to expand support for research.

HDSA hopes to issue its first call for proposals in early 2013, Dr. Yohrling said.

HDSA also will continue to support an important consortium of HD stem cell researchers, he noted.

A pivotal player

Dr. Yohrling’s diverse experience in HD research makes him a pivotal player in the search for treatments.

After receiving his Ph.D. in pharmacology from Wake Forest University in 2000, he became the very first post-doctoral researcher in the lab of Jang-Ho Cha, M.D., Ph.D., at Harvard Medical School/Massachusetts General Hospital. (Dr. Cha is a member of the HDSA Board of Trustees and will chair the HD Human Biology Project Advisory committee.) During his two years under Dr. Cha, he “got to see and interact with HD firsthand.”

“Any human being with a soul in their body” would be motivated to help, Dr. Yohrling recalls of his initial, serendipitous contact with Dr. Cha and the HD team while in Boston searching for a post-doctoral position. “I was hooked. I felt it was my calling.”

Under Dr. Cha, Dr. Yohrling also received an HDF grant.

Dr. Yorhling spent the next five years conducting Alzeimer’s disease research at the pharmaceutical giant Johnson & Johnson, followed by two years at Galleon Pharmaceuticals, Inc., researching respiratory conditions.

In 2009 Dr. Yohrling joined CHDI, which he described as a “dream” of an opportunity to focus fully on HD research in a large, resource-rich organization. There he served as director of target assessment and then director of systems biology-pathway assessment. Working with firms and leading HD scientists, he managed millions of dollars in research contracts. He also led the development of HD Research Crossroads, an online repository of HD-relevant drug target validation data.

Impacting patients with ‘all hands on deck’

CHDI was “more a behind-the-scenes operation,” Dr. Yohrling observed. “HDSA is more of a grassroots, family-oriented foundation. The opportunity to get back to that, while also getting involved in human biology research, was an opportunity too good to ignore.”

Responding to the argument that HDSA should let others concentrate on research while putting funds strictly into social services, Dr. Yohrling observed that the HDSA board and HD families want the organization “back involved in research and not to leave it up to the other entities like CHDI, HDF, and the government,” although his key responsibilities will include maintaining “an open line of communications” with those and other HD research organizations.

“We’re really glad to have someone like George working at HDSA,” said Robi Blumenstein, the president of CHDI Management, Inc., which carries out the day-to-day tasks of CHDI’s mission. “It just furthers our ability to collaborate.”

“I think that HDSA is well-positioned with their centers of excellence around the country,” Dr. Yohrling continued. “This is an incredible resource. It’s a huge benefit that HDSA has over other foundations or organizations, this access and close connection to the patients. A research program, although it might be limited initially, if the money is use properly and thoughtfully, can have a huge impact on the lives of patients.”

“We need all hands on deck,” said Vetter, adding that everybody in the HD community can take small but important steps to help the cause by keeping in touch with attending physicians, learning about HD research, and participating in clinical trials and research studies. “As we look at the dawn of a new time of HD therapeutic development, the only way those drugs are going to come to market is if people get involved. Getting involved is the most important thing that the HD community can do right now.”

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) 

The definitive step out of the Huntington’s closet

Today I take my most definitive step out of the terrible and lonely “Huntington’s closet”: using my real name, I have published an article about my struggle against HD in a mainstream media outlet.

Titled “Racing Against the Genetic Clock: A historian carrying the gene for Huntington’s disease hopes to galvanize increased support for brain research,” the article appears in today’s online edition of The Chronicle of Higher Education. It will also appear in the November 9 print edition.

“Scholars often shift focus over the course of a career to pursue a discovery, a new job, or a need for variety,” begins the article, which explains my exploration of the history of science as a way to expand both my advocacy and career. “For me, it was learning that I will, at some point, develop a terrifying, untreatable, fatal brain disorder.”

With great sadness, I wrote of my mother’s demise, the discovery that I had inherited the HD gene from her, and my ongoing advocacy to raise awareness and increase funding for research towards treatments.

“At 52, I have reached my mother's age of onset,” I conclude. “I cherish each moment of health. As I contemplate my intellectual legacy, I encourage others to join the race to protect our most important natural resource – our brains – and strive for a world in which science conquers disease.”

You can read the full article by clicking here.

For the public, and in my professional circles, I willingly share that that Gene Veritas is Kenneth P. Serbin. I will still write this blog as “Gene Veritas” (the “truth in my genes”), my trademark in the HD world, the persona that in many ways symbolizes the struggles of our community and, indeed, all disease-gene carriers.

Gene Veritas, aka Kenneth P. Serbin, at Alnylam Pharmaceuticals in 2011.

An arduous and painful transition

I had hid in the HD closet ever since my mother’s diagnosis in late 1995.

Many times I wanted to shout out to the world about my mom’s terrible downfall and my own potentially frightening future with the disease, but, fearful of genetic discrimination, I always kept quiet, swallowing my difficult feelings about HD.

In 2010, however, after the passage of federal health care and anti-genetic discrimination legislation, I started making public speeches about my predicament.

My gradual exit from the HD closet has proved arduous and painful.

On October 25, the day I received the news of my article’s acceptance for publication, and for a few days thereafter, I felt especially overwhelmed and apprehensive.

I thought of how tens of thousands of Chronicle subscribers will have access to my article, and many more people may read it by simply viewing it for free on the publication’s website.

Above all, I worried about how to tell my co-workers and superiors. With the Chronicle article, I will be deliberately demolishing the near-perfect firewall that I painstakingly constructed between my professional life and HD advocacy.

Some may be shocked to learn of this hidden dimension of my life, and they will likely worry about me, too.

Luckily, when I inform them about the article, I’ll also tell them that my latest checkup with my neurologist, on October 30, ended with a clean bill of health on the HD front. I’m not required to do so, but, after revealing the terrible symptoms I could suffer, I also want them to know of my success so far in remaining asymptomatic (click here to read more).

Controlling my own story

In the last few days, however, I achieved a sense of calm, and, in the final hours before the publication, even a bit of jubilation.

I’ve been able to rely on my wife, close friends, and members of the HD Facebook community for moral support.

In anticipation of the article’s appearance, I actively sought their advice about how to reveal the article to my colleagues. They’ve all helped me put this moment in perspective.

For those who advised against coming out, I’ve described the Chronicle piece as a “preemptive strike.” Rather than let others learn about my HD status by stumbling upon it on the Internet, hearing through the rumor mill, or becoming aware only when my symptoms start, I am taking the initiative to “control the narrative of my own story” about HD.

This approach provides me with the opportunity to properly educate friends and colleagues about HD and perhaps even build a support network to assist me should I become disabled.

Feeling lighter

Although this definitive step out of the closet remains a momentous event for me, I have come to see it as an opportunity to expand the Huntington’s cause and to help defeat the very stigma of HD that originally sent me fleeing into the closet.

I will also feel immense relief and joy at being able to talk openly about HD at any time and with any person.

In discussing the Chronicle piece with a close professional colleague and friend the other day, I was thankful to hear his prediction that this experience, fraught with so much doubt  about the balance between advocacy and privacy, would ultimately bring me closer to my wife.

Indeed, far too much of our energy has gone into insulating ourselves instead of reaching out for the support we need on a personal level and in terms of the cause.

I nearly cried after my friend assured me that I would feel an immense burden lifted from my shoulders.

“You’re going to feel lighter,” he said with confidence.

Amen to that!

I know the road ahead is unpredictable, and that I will feel many things besides lighter, but for now, I’m just glad I can tell people how I’m racing against the genetic clock.

( I dedicate this article to the memory of my mother Carol Serbin, who died on February 13, 2006, after a long battle against HD, and of my father Paul Serbin, the “HD warrior” who tirelessley cared for her for more than ten years and who died with a broken heart on September 25, 2009. I know my parents would have been proud of my Chronicle article.)