This Thanksgiving, appreciating stable health and new plans for Huntington’s disease advocacy

This Thanksgiving, I am especially grateful for good health – and all that it enables me to enjoy.

At my annual neurology checkup on October 31, the doctor told me that I remain asymptomatic for Huntington’s disease. My more extensive annual Enroll-HD examination earlier in the year also showed no symptoms. 

I tested positive for the HD gene in 1999. Next month, I turn 59. At that age, my mother had already been diagnosed and was rapidly losing the ability to walk, talk, and care for herself. She died in 2006 at the age of 68 after a long struggle.

I never imagined that at this point I could still pursue my passion for writing, teach at the university, and support my family.

As I frequently tell students, colleagues, and my family, “health is first.” Without it, achieving goals and handling responsibilities can become very difficult, if not impossible.

Studying the history of the HD cause

I am putting the final touches on a book in my field of Brazilian history, scheduled to be published next June, From Revolution to Power in Brazil: How Radical Leftists Embraced Capitalism and Struggled with Power. I began the research more than two decades ago, not long after learning of my mother’s HD diagnosis. Seeing the project come to fruition is thrilling and profoundly fulfilling.

With the Brazil project complete, I will carry out my long-gestating plan to shift my main scholarly focus to the history of science, technology, and medicine. Last month I proposed a new, multi-year research project, titled “Racing Against the Genetic Clock: A Social, Scientific, and Personal History of the Huntington’s Disease Movement.”

I aim to study how key facets of the movement intertwined with major developments in the biotechnological and medical revolutions of the past 200 years. I believe that the HD cause can serve as a guidepost for other disease communities and inform key bioethical questions related to them.

I also want to help the HD community reflect on its path through history. 

More than ever, my scholarly work and HD advocacy will meld. (Click here to read more.)

Seeing our daughter enter college

On a personal level, good health allowed me to join my wife Regina last August in helping our HD-free daughter Bianca set up for her first semester at the University of Pennsylvania, where she is studying in its College of Arts and Sciences.

I had always feared that HD would prevent me from experiencing this special moment – just as HD had stopped my mother from interacting with Bianca as a baby and young child.

I am more determined than ever to see Bianca graduate from college and find her way in life. I’m hoping that GENERATION HD1, the historic Roche Phase 3 clinical trial of a gene-silencing HD drug, will result in an effective treatment not only for patients, but as a preventive measure for presymptomatic gene carriers like me. Roche hopes to enroll the first volunteers starting in early 2019.

Looking ahead, I hope to retire on my own timeline – not because of HD.

Regina, Bianca, and Kenneth Serbin (aka Gene Veritas) during Penn Family Weekend, October 21, 2018 (family photo)

The preciousness of life

I’ve been extremely fortunate to reach this point without HD symptoms—or other significant health problems. Many HD brothers and sisters of my generation are struggling with symptoms. 

Like so many in HD families and other difficult situations, I’ve learned to value each moment of life.

Others face different health issues. At this time last year, I lost two wonderful friends about my age, generous supporters of the HD cause, taken quickly and unexpectedly by other conditions. I’ve missed them dearly, and think about them daily as a reminder of the preciousness of life.

Tomorrow, I want to enjoy Thanksgiving.

God and nature willing, I’ll awake the next day ready to love my family, continue the fight to defeat HD, and dream of a day when a cure frees me to assist people less fortunate.

Happy Thanksgiving! And the best of health for you and yours.

Ionis Phase I Huntington’s disease trial at halfway mark: ‘No surprises so far’ means good news

At its halfway mark, Ionis Pharmaceuticals' historic Huntington’s disease Phase 1 gene-silencing clinical trial is on track to finish as scheduled in late 2017, company officials said in an interview on September 26.

“What we can say is that the trial is going well,” said Frank Bennett, Ph.D., Ionis senior vice president of research and the franchise leader for the company’s neurology programs.

Dr. Bennett added that no “issues” have arisen so far in the Phase 1 safety and tolerability study of its drug IONIS-HTT_Rx in patients with early HD. IONIS-HTT_Rx aims to reduce the production of huntingtin protein in brain cells. This approach, if it advances to Phases 2 and 3, may have the potential to slow, halt or perhaps even reverse the progression of HD symptoms. The trial began in September 2015, with participants in England, Germany, and Canada.

The Ionis HD team explained that the Phase 1 trial is not assessing the drug’s efficacy. Each patient in the trial receives the drug for just three months – not long enough to gauge any impact on symptoms.

Furthermore, the trial is “double-blinded”: trial participants, trial administrators, and Ionis scientists do not know who is getting the drug or a placebo. This insures that bias and other external factors don’t affect the trial results.

Nevertheless, the absence of problems is good news.

No surprises have occurred to date, commented Anne Smith, Ph.D., the Ionis director of clinical development and the individual responsible for the day-to-day management of the trial.

“It’s blissfully quiet,” Dr. Smith said. “You don’t want surprises in clinical trials. Most surprises in safety trials are bad surprises. This one is surprise-free to date.”

Also, trial participants had no difficulties with the delivery of the drug via injections into the spine (so-called intrathecal injections), added Roger Lane, M.D., the Ionis vice president for neurology clinical development and one of the designers of the trial.

Watch my reaction after the interview at Ionis headquarters on September 27 in the video below.

Ionis Phase I HD Trial at Halfway Mark: 'No Surprises So Far' Means Good News from Gene Veritas on Vimeo.

Phase 2 could start in 2018

“We’re continuing to enroll patients in the study,” Dr. Bennett said. A total of 36 patients divided into four cohorts – each subsequent cohort taking a higher dose of IONIS-HTT_Rx – will participate in the trial.

Ed Wild, M.D., Ph.D., one of the administrators of the trial at University College London, announced in June at the annual convention of the Huntington’s Disease Society of America in Baltimore that the third cohort had received permission to receive the drug. (Click here to watch a video of Dr. Wild’s presentation.)

“This is a new therapy, and we want to make sure that we’re doing no harm,” Dr. Bennett emphasized. “Everything is geared towards the safety of the drug at this stage.”

If Phase 1 confirms safety and tolerability, a year-long Phase 2 trial to measure efficacy in a larger number of patients likely would start in 2018, Dr. Bennett said.

Infants on an Ionis SMA drug living longer

The update provided by the Ionis HD team came in the wake of further validation of the company’s scientific approach.

Ionis makes antisense oligonucleotides (ASOs, artificial strands of DNA) that alter the expression of genes and can therefore potentially serve as treatments for genetic diseases. On August 1, Ionis and its partner Biogen actually halted a Phase 3 trial of an Ionis ASO (nusinersen) in infants with spinal muscular atrophy (SMA) because the drug, which increases the level of a key protein, was working so well.

On September 27, Biogen announced that it had completed its application for priority review of nusinersen by the U.S. Food and Drug Administration (FDA).

Like HD, SMA is a genetic neurodegenerative disorder. It primarily affects children, who “end up becoming paralyzed over time,” Dr. Bennett explained, and become vulnerable to respiratory infections or other diseases. Children diagnosed with the most severe form of SMA generally live less than a year, he said. In a less severe form of SMA, children lose the ability to walk over time as they grow up, Dr. Bennett added.

“I think the surprising thing that we found – and this was evidence early in the program – was that we didn’t just stop the decline in these patients, but we actually reversed it,” Dr. Bennett said. “That was really unexpected. I should say that they’re not cured of the disease, but they’re doing much better now than expected. They are surviving longer based on the natural history of the disease.”

These results demonstrated the body’s capacity to mend once the cause of a disorder is removed, he observed.

“We’re hopeful that will also occur in Huntington’s,” Dr. Bennett affirmed. “We have to demonstrate it, but I think there’s a precedent now in these neurodegenerative diseases. If you remove the insult or the toxicity, you can recover function.”

Dr. Frank Bennett of Ionis makes a point during discussion of the company's Phase 1 clinical trial for a Huntington's disease treatment (photo by Kristina Bowyer, Ionis)

Preparing for the HD clinical study

In the Phase 1 IONIS-HTT_Rx trial, clinical trial investigators are collecting some information about the drug’s effect on biomarkers (indicators of a disease mechanism or drug impact) that may help the team design a potential Phase 2.

According to Dr. Lane, before a patient receives each of the four planned doses, the trial administrators collect samples of cerebrospinal fluid (CSF) that will be used to measure levels of huntingtin protein and a variety of other protein markers of neuronal injury and inflammation. Patients also undergo brain scans to look at the volumes of, and the connectivity between, different parts of the brain that are known to be affected in HD.

Another biomarker is neurofilament, described by Dr. Bennett as a protein involved in the cytoskeleton or internal “scaffold” of neurons.  “It’s something very specific to neurons,” said Holly Kordasiewicz, Ph.D., the Ionis director of neuroscience drug discovery, who participated in selecting the ASO, researched it in animals, and is developing biomarker tests for the Phase 1 study. “When the neurons are damaged, neurofilament is released. In a number of neurodegenerative diseases, neurons are dying and neurofilament levels go up.”

In HD, brain cells die. In a clinical study, a decrease in neurofilament would suggest that the drug is protecting neurons, Dr. Kordasiewicz added.

Ionis Huntington's disease clinical trial planners Dr. Anne Smith (left), Dr. Roger Lane, and Dr. Holly Kordasiewicz meet with Gene Veritas (in green shirt) on September 26, 2016, to provide an update on the company's Phase 1 HD trial (photo by Kristina Bowyer of Ionis)

Getting the design of Phase 2 right

The participants in the IONIS-HTT_Rx study undergo a battery of tests that assess memory, thinking, movement, behavior problems, and abilities to perform every-day activities. This is in preparation for use of such measures in a potential Phase 2.

“We’re trying to get the information to design the best efficacy study that we can,” said Dr. Kordasiewicz. “A really sad outcome would be failure of an efficacy study due to the wrong design, not because the drug’s not working. You have to be sure you’re picking the right dose and the right endpoints for the efficacy study.  That’s why all the extra stuff goes into these Phase 1 trials, so that you can get the design right and have the best shot at giving the drug the best chance at working.”

The large burden of work on patients and trial administrators in Phase 1will ultimately allow Ionis (and its partner Roche) to “simplify” potential Phase 2 and 3 trials, making them quicker and making it easier for patients to participate, Dr. Bennett added.

Seeking answers to key questions

This is the first time that an HD gene-silencing drug is going into the human brain. In animals such as mice and non-human primates, the drug gets into both the cortex (the outer, main part of the brain, linked to consciousness) and the striatum (a part of the brain deep under the surface that is involved in movement). Both areas are affected by HD.

A key question for researchers: must IONIS-HTT_Rx reach the striatum to help alleviate HD?

According to Dr. Kordasiewicz, the latest research in HD mice (conducted by William Yang, M.D., Ph.D., of the University of California, Los Angeles) demonstrates that silencing the huntingtin gene in the cortex was more effective than silencing the gene in the striatum, but that silencing in both cortex and striatum was the most effective approach.

Another concern of scientists and HD patients and their families involves the abilities of the ASO, or gene-silencing drug. Should the ASO be designed to reduce only the so-called “bad,”mutant huntingtin? Or is it okay to reduce both the bad and the normal version, which is inherited from the unaffected parent? The IONIS ASO is expected to do the latter.

According to the Ionis HD team, the controversy over this question is diminishing. Studies in animals support the safety of approaches that reduce both mutant and normal huntingtin.  Additionally, Dr. Guohao Wang’s work in mice showed that eliminating huntingtin completely in later life did not have any adverse consequences.

“That was good evidence to support our approach,” said Dr. Lane.

Involving the U.S., thanking patients and families

Many in the HD community have asked: why didn’t Ionis conduct Phase 1 in the United States? And would a potential Phase 2 include Americans?

“I’d be surprised if the U.S. wasn’t involved in a Phase 2 study, as well as additional countries, but I don’t think we are in a position to say specifically which countries are going to be involved,” Dr. Bennett commented. “There were strategic decisions that caused us to go to Europe and Canada first. It’s not that we want to ignore the U.S.” He explained that it was faster to start a trial in Canada and Europe.

The Ionis HD team thanked the Phase 1 participants and their families for their involvement in the Phase 1 study.

“It’s been a very good community and very supportive of our efforts,” said Dr. Bennett. “We also want to thank them for their patience.”

(Disclosure: I hold a symbolic amount of Ionis shares.)

(Click on the links below for past coverage of the Ionis HD project.)

Chief Huntington's disease drug hunter: 'every confidence first treatments' in the works

Huntington's disease patients get first dosing in historic Isis Pharmaceuticals' gene-silencing drug trial

Isis Pharmaceuticals launches historic clinical trial to silence Huntington's disease gene

Moving toward a potential treatment: Isis, CHDI researchers outline upcoming Huntington's disease gene-silencing trial

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

Quickening the pace towards a Huntington's disease gene-silencing clinical trial: pharma giant Roche, Isis enter partnership

Designing the best drug possible to defeat Huntington's disease

Building a 'laser-guided missile' to attack Huntington's disease

Observing the cure in progress 

Defeating Huntington’s disease starts with taking care of yourself and joining Enroll-HD

For those of us affected by Huntington’s disease or at risk for it, the fight against the disorder begins by taking care of ourselves.

This idea occurred to me during my daily morning meditation on Jan. 14, 2016, as I anticipated my annual checkup in the Enroll-HD program later that day.

Many people struggling to come to terms with HD ask: with so much to worry about, how can I contribute to the cause?

You can start simply by committing to care for your health and asking family members and others to help monitor your condition. In doing so, you will help your family, too, by preparing for and perhaps even diminishing the current or eventual caregiving burden associated with Huntington’s.

You can extend that assistance to the entire HD community by joining Enroll-HD, a worldwide registry of affected individuals, asymptomatic HD gene carriers, untested at-risk individuals, and other family members. With its growing database, Enroll-HD serves as a platform and research project aimed at facilitating clinical trials and the discovery of treatments.

The greater the participation in Enroll-HD, the faster trials can take place.

Helping the researchers

Not long after learning of my own risk for HD in 1995, I started participating in research projects based at the University of California, San Diego (UCSD), and San Diego State University (SDSU) (click here to read about one example).

In January 2015, shortly after my participation in the PREDICT-HD study ended, I registered in Enroll-HD.

At this month’s follow-up visit at the UCSD Huntington’s Disease Clinical Research Center, I once again gave blood that scientists can use in the numerous research projects facilitated by Enroll-HD. I also underwent a battery of cognitive tests.

In addition, I participated in four research projects by scientists at UCSD, SDSU, and other local institutions. Two involved standing on high-tech platforms designed to detect  balance problems in people who have brain disorders and concussions. Another involved a measure of fine motor skills, which are seriously affected in HD, by writing on a special tablet connected to a computer.

Finally, I spit into a tiny collection tube for a project involving the detection and study of the huntingtin protein in saliva. Abnormal huntingtin causes HD.

Gene Veritas (aka Kenneth P. Serbin) writing on an experimental tablet (above) and standing on a platform to detect balance problems (below) (photos by Ayesha Haque)

A neurological exam

My visit concluded with a standard neurological exam by Jody Corey-Bloom, M.D., Ph.D., the director of the UCSD clinic. Among other tasks, I had to follow her fingers with my eyes, rapidly tap together my thumb with my index and middle fingers, and walk down a straight line for about 25 feet.

To my great relief, Dr. Corey-Bloom noted no irregularities! At 56, I am now past the point at which my HD-stricken mother displayed the characteristic involuntary movements.

Afterwards, I discussed with Dr. Corey-Bloom my questions and concerns about my potential participation in the SIGNAL clinical trial to test a monoclonal antibody as an HD treatment.

I will soon provide an update on SIGNAL.

Enroll-HD’s positive impact

The next day, I obtained the latest news about Enroll-HD from Joe Giuliano, the director of clinical operations for CHDI, the multi-million-dollar nonprofit virtual biotech aimed exclusively at developing HD treatments. In collaboration with HD research centers and clinics around the globe, CHDI sponsors Enroll-HD.

Enroll-HD officially launched in July 2012. According to Giuliano, as of January 15, nearly 9,000 individuals from 14 countries and 140 sites had signed up.

Has the program met CHDI’s expectations?

“I think there’s a high level of engagement among the patient community and among the investigators around the world,” he said during a phone interview. “The recruitment has been excellent. We could have 10,000 participants by the end of March, which would be amazing. I’m really pleased with how well the availability of the dataset and the biological samples [blood] has worked out. In other words, people are using the data, and the data is available through the website. It’s a great example of making data available quickly.”

What’s been the impact?

“We’ve been actively assisting three clinical trials that have been going on – PRIDE, Amaryllis, and LEGATO – with their recruitment,” Giuliano continued. “We have released our second periodic dataset, with 4,150 participants. There are 28 projects that are currently using Enroll-HD data, to answer different research questions. We’ve been actively distributing biological samples for a variety of projects.”

As a result of Enroll-HD, scientists are deepening their understanding of the disease, and doctors are finding ways to improve care.

Enroll-HD contributes directly to the quest for treatments. The larger the number of potential clinical trial volunteers, the greater the chance that trial administrators can enlist the required number for each trial. The number of HD trials has increased each year, increasing the demand for volunteers. Without the trials and the volunteers, scientists can’t test treatments.

Joe Giuliano (left) and Gene Veritas at a 2015 CHDI conference

Challenges in Latin America

On the downside, in one key region, Latin America, Enroll-HD has progressed “very slowly,” Giuliano said. So far, Enroll-HD is only operating in Argentina and Chile.

In October 2015, the National Research Ethics Commission in Brazil – the world’s sixth largest nation, with an estimated 20,000 HD-affected individuals – rejected the proposal to set up Enroll-HD there.

“Obviously we were very disappointed,” Giuliano said. “I think the National Research Ethics Commission rejected based on some areas where there was a perception that the Enroll-HD study was not aligned well with some of Brazil’s legal precedents.”

However, Giuliano said that Enroll-HD will step up efforts to involve Latin America’s HD families. With growing interest in Colombia, that country be the next to join Enroll-HD, he said.

“We’re working harder than ever,” Giuliano affirmed. “You haven’t heard the end of us in Brazil. We’re really committed to Latin America. Many of us believe that Latin America, like in the beginning of their history of HD research in Venezuela, which played an important role – now in the later stages of HD research it’s going to resurge, reawaken, and become an important player in HD research again.”

In a future article I will explore the Brazil decision in depth as well as ways HD families can push for greater acceptance of Enroll-HD there and in other countries of the region.

Building a common cause

As I approach the inevitable onset of HD and feel many of the other effects of normal aging, I realize more than ever the need to stay in shape via a healthy diet, daily stretching and aerobics, meditation and spirituality, and psychotherapy.

Without health, I cannot work, dedicate myself to my family, or advocate for the HD cause.

Caregivers, the "HD warriors" who enter the trenches each day, must also seek opportunities for respite.

With the significant progress towards HD treatments of recent years and growing awareness of the importance of HD and other neurological disorders, advocates have a busier agenda than ever.

I am thrilled to assist HD research and the implementation of the critical clinical trials by taking part in Enroll-HD.

After following the HD movement in Brazil for two decades and participating in the historic sixth World Congress on Huntington’s Disease there in September 2013, I aim to join my Brazilian HD brothers and sisters to advocate for reconsideration of the government’s rejection of Enroll-HD.

We must not lose the momentum in Brazil and Latin America!

Only by building this common cause can we ultimately defeat HD.

Isis Pharmaceuticals launches historic clinical trial to silence Huntington’s disease gene

Isis Pharmaceuticals, Inc., based in Carlsbad, CA, has launched its long-awaited clinical trial to test a drug designed to attack Huntington’s disease at its genetic roots.

In a July 21 press release, Isis said it had initiated a Phase I human clinical study of ISIS-HTT_Rx, its compound aimed at diminishing the symptoms of HD. HTT_Rx signifies a medication for HD. The disease is caused by a defect in both the huntingtin gene and protein, which are symbolized by the letters htt.

“ISIS- HTT_RX is the first therapy to enter clinical development that is designed to directly target the cause of the disease by reducing the production of the protein responsible for HD,” the release stated.

In partnership with Roche, the Switzerland-based pharmaceutical giant sharing costs of the typically expensive clinical trial, Isis thus becomes the first entity to use a gene-silencing technique in the attempt to stop HD.

“Although the toxic protein produced from the huntingtin (HTT) gene in HD patients has been a target of interest for many years, no therapies have advanced to clinical trials to treat the underlying cause of the disease,” Frank Bennett, Ph.D., Isis’s senior vice president of research, stated . “Our antisense technology has enabled us to discover and develop ISIS-HTT_Rx, the first therapeutic approach designed to treat the genetic cause of HD."

Frank Bennett, Ph.D., of Isis Pharmaceuticals (photo by Dr. Ed Wild)

A ‘significant milestone’

HTT_Rx is an antisense oligonucleotide, an artificial strand of DNA created by Isis to block the action of the RNA molecules that translate the huntingtin genetic code to make the huntingtin protein.

Involving about 36 early-stage HD patients at about six sites in Europe and Canada, the Phase I trial focuses on the safety and tolerability of HTT_Rx. According to an Isis spokesperson, the sites will start recruiting participants as early as in a few weeks.

Depending on the pace of recruitment, Phase I most likely will end in 2017. If Phase I is successful, a larger Phase II trial to test efficacy likely would take place in 2018. A successful Phase II trial would be followed by a Phase III trial. Together all three phases of a clinical trial program typically take at least five years.

Last August, scientists from Isis and CHDI Foundation, Inc., the nonprofit virtual biotech firm that funded the early stages of the Isis research starting in 2007, provided extensive details about the plans for the trial. (Click here to read more.).

“The initial development of this antisense drug for Huntington’s disease came out of a longstanding productive partnership between Isis and CHDI, and its advancement now to clinical trial is testament to Isis’ perseverance and scientific expertise,” CHDI president Robi Blumenstein stated in the press release. “It’s exciting that therapeutic candidates grounded in the biology of Huntington’s disease are finally making their way to clinical trial.”

“The initiation of the ISIS-HTTRx study is a significant milestone in the history of Huntington's disease research as this marks the first time a drug designed specifically for Huntington's patients has transitioned into the clinic,” George Yohrling, Ph.D., senior director for mission and scientific affairs for the Huntington’s Disease Society of America (HDSA), wrote in an e-mail. “My hope is that this study not only shows that the drug is safe, but serves as an informative beacon for all future huntingtin-lowering trials.”

Martha Nance, M.D., the director of the HDSA Center of Excellence at Hennepin County Medical Center in Minneapolis and a member of the executive committee of the Huntington Study Group, said that “it would be impossible to overstate the importance of this trial.”

“I am old enough to have grown up in the 1960s, swept up as a young child with the excitement of space exploration, and I remember, almost as clearly and importantly as the Apollo 11 mission that actually LANDED on the moon, the Apollo 8 mission over Christmas 1968, during which William Anders took the iconic picture of the earthrise over the moon,” Dr. Nance wrote in an e-mail. “There were several more steps, several more Apollo missions, before Neil Armstrong could jump off the ladder onto the moon. The ISIS study is the HD equivalent of the Apollo 8 mission.”

LaVonne Goodman, M.D., the founder of Huntington's Disease Drug Works, said that there are "high hopes and expectations" about the trial. "We celebrate those individuals with HD, heroes who are selflessly participating in this trial and all others, 'taking one for the team,'" she wrote in an e-mail.

“We’re very enthusiastic about the drug,” Dr. Bennett said in a 2014 interview.

As he put it previously, Isis technology is like a “laser-guided missile” that targets a specific, disease-causing messenger RNA and destroys it or takes it out of the body “so that you don’t produce that messenger RNA.”

The Isis-Roche partnership

According to the press release, with the initiation of the clinical trial, Isis – a small company – earned a $22 million milestone payment from Roche. To date, Isis has earned $52 million in upfront and milestone payments from the partnership. It can earn more as the project progresses, as well as royalties on potential sales.

Roche can exercise the option to license ISIS- HTT_Rx from Isis through the completion of the Phase 1 trial. If so, Roche will assume responsibility for global development, the acquisition of regulatory approvals, and marketing the drug.

The partnership is critical. Isis cannot alone afford to carry out a clinical trial. Drugs usually cost hundreds of millions of dollars to develop.

According to the press release, Isis’s drug projects include 38 drugs aimed at treating a wide range of diseases, among them cardiovascular disease, metabolic disorders, cancer, and severe and rare diseases, including neurological disorders such as HD.

A huge dose of hope

The announcement of the historic trial’s launch provides a huge dose of hope for the HD community.

Since the discovery of the huntingtin gene in 1993, scientists have published thousands of research papers on HD and identified hundreds of potential “targets” for treatments.

In recent years, scientists and drug companies have initiated an increasing number of clinical trials in the quest for effective treatments. However, to date none has proven successful in halting the disease.

A necessary leap

As seen in animal studies, the infusion of HTT_Rx into the brain has led to the disappearance of the HD-like symptoms.

Scientists warn that it’s a still a huge leap from animals to humans when it comes to testing drugs. Also, only about one in ten clinical trials results in a drug reaching the market.

Earlier this year prominent HD specialist Bernhard Landwehrmeyer, M.D., Ph.D., cautioned that it could still take decades for the gene-silencing approach to play an effective part in managing the disease.

“We should all be extremely excited and hopeful, but remember that there is a lot of work ahead for researchers, doctors, patients, and families before we will get to our moon, and no guarantee of success,” wrote Dr. Nance.

Nevertheless, the Isis-Roche trial is a major step. At a minimum, it will help answer key questions about the gene-silencing approach.

If it is successful in ameliorating symptoms, it could mean the beginning of the end of Huntington’s disease as a threat to the tens of thousands of families affected worldwide.

* * *

Below see links to previous reports on Isis.

"Moving toward a potential treatment: Isis, CHDI researchers outline upcoming Huntington's disease gene-silencing clinical trial"

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

"Quickening the pace towards a Huntington's disease gene-silencing clinical trial: pharma giant Roche, Isis enter partnership"

"Designing the best drug possible to defeat Huntington's disease"

"Building a 'laser-guided missile' to attack Huntington's disease"

"Observing the cure in progress"

Also see coverage at HDBuzz by clicking here.

(Disclaimer: I hold a symbolic number of Isis shares.)

The Huntington’s disease community can’t afford to lose momentum

The Huntington’s disease community can’t afford to lose momentum in the quest for treatments for this incurable disorder.

As I noted in my last article, fatigue can set in for advocates and family members. This is understandable, given the tiring demands of caregiving, the frequent feelings of hopelessness in the face of the “devil of all diseases,” and the immense challenge faced by scientists – and the population needed to participate in drug trials – in devising revolutionary drugs that reach the brain and prevent its cells from dying.

Interrupting my own momentum in writing a book in my field as a Brazil specialist, I summoned the strength to once again focus on HD. I traveled coast-to-coast twice in a little more than 72 hours to give a speech about a crucial upcoming HD clinical trial and to interview a prominent scientist engaged in the search for treatments. It was an intense time.

My trip on April 10 began inauspiciously, as a late departure from San Diego caused us to approach Atlanta as thunderstorms struck, leading the flight to detour to Birmingham, AL. Arriving in Atlanta close to midnight, I had missed my connection to Providence. After finally finding a hotel 20 miles from the airport, I could only sleep four hours. The morning flight to Providence also left late, because of tardy pilots.

Travelers do face such stresses, especially as service in the airline industry declines, but as a carrier of the HD gene mutation concerned about disease onset, I especially need to avoid them.

As it became clear that I would miss my 9 a.m. keynote talk on April 11 in Norwich, CT, Laura Kokoska, an advocate for the Connecticut affiliate of the Huntington’s Disease Society of America (HDSA-CT) whose mother has HD, helped me via cell phone calls and texts to calmly consider alternatives. She and another advocate, Val Kim, whisked me from Providence to Norwich, serving me lunch in the car. We arrived in time for me to speak in the last slot of the day.

The audience of some 30 was anxious to hear me provide an HD family member’s perspective on one of the most significant steps towards treatments since the discovery of the huntingtin gene in 1993: the Roche/Isis gene-silencing trial, set to start this year at several sites in Canada, England, and Germany.

HDSA-CT education event participants (from left to right): James McGann, Debbie Pausig, Gene Veritas (aka Kenneth Serbin), Laura Kokoska, Holly Broadbent, and Sue McGann

A historic attack on the genetic roots

I first explained how my mother’s demise from HD and my positive test for the genetic mutation in 1999 led me to delve into the science of Huntington’s disease. Then I described how since early 2008 I have tracked the program by Isis Pharmaceuticals, Inc., to stop HD at its genetic roots. In 2013 Isis partnered with the pharmaceutical giant Roche to prepare for a gene-silencing clinical trial in HD.

“This trial is a historic trial,” I said. “It’s a big moment in the history of our community, and also in the history of science.”

Isis and Roche aim to test a drug known as an antisense oligonucleotide (ASO). “That’s a fancy term for basically saying it’s an artificial piece of DNA,” I continued. “That is [a] ‘laser-guided missile’ that is supposed to go into the brain cells, and it will block the production of the huntingtin RNA and the protein.[…] The protein is what is causing the problems in the cell. They’re also thinking now that the RNA is also causing problems within the cell, that they want to cut down the amount of the RNA, too.

“This clinical trial […] is the first time that someone is going after the genetic roots of the disease,” I stressed. “That is an immense motive for hope in our community.” And that’s why I’m so excited about the project and follow it so closely.

Being realistic

I showed PowerPoint slides of photos of the Isis facility and the company’s scientists, including Frank Bennett, Ph.D., the senior vice president for research and the head of the HD project. I also noted the important support for the project from CHDI Foundation, Inc., and the lab of Donald Cleveland, Ph.D., at the University of California, San Diego.

I reminded the audience that enthusiasm must be coupled with patience: the HD community must recognize the time it takes to develop drugs and also brace itself for failures in the quest for treatments. This year Isis and Roche are initiating Phase I of the trial, aiming only to test the safety and tolerability of the ASO.

Potential Phases II and III would examine the drug’s efficacy. In all, it could take five years or more to complete all three phases.

“We have to be realistic,” I said. “Ninety percent of drugs that go into clinical trials do not make it to market.[…] It takes a lot of shots on goal before you finally get a goal.[…] We have to keep in mind that it’s a slow, painstaking, and deliberate process.”

You can watch my speech in the video below.

Hope for Huntington’s Disease Families: The Isis/Roche Gene-Silencing Clinical Trial from Gene Veritas on Vimeo.

Returning to Yale

After the event I rode to New Haven with Debbie Pausig, a marriage and family therapist, grief counselor, and HDSA-CT support group leader. Debbie recently published An AffaiR Worth Remembering With Huntington’s Disease: Incurable Love & Intimacy During an Incurable Illness, a memoir of her relationship with her late, HD-stricken husband. Debbie capitalized the “r” in “affair” – and it’s reversed on the cover of the actual book – to emphasize the many unusual twists in her story.

Later I visited the campus of Yale University, my alma mater, and ate pizza at an old haunt. It was only the fourth time I’ve returned to Yale since graduating with a B.A. in history in 1982. In 2012 I visited Yale to interview a number of scientists working on HD (click here to read more), including the preparation of clinical trials.

“Felt like an undergrad again walking through freezing campus,” I texted an old classmate while watching the students and remembering the exhilarating possibilities of youth.

In my hotel room, mixing in baking soda and Epsom salt from a care package put together by Laura, I relaxed in a hot bath. As Laura put it, the bath would help my body recover from the traumatic plane trip.

Gene Veritas (aka Kenneth Serbin) outside Wall Street Pizza (formerly Naples) in New Haven

A science tour and lunch with old friends

The next morning I took a tour of Yale’s Magnetic Resonance Research Center with its long-time director, Doug Rothman, who received his Ph.D. from Yale in 1987. A professor of diagnostic radiology and biomedical engineering at the Yale School of Medicine, Dr. Rothman is one of the world’s leading pioneers in research in MRI, magnetic resonance spectroscopy, and quantitative neuroscience with magnetic resonance.

A future article will detail my interview with Dr. Rothman about his research into key questions about the mitochondria, the powerhouses of our cells, and their role in HD.

I lunched with classmate Paul Bass and his wife Carole (Yale 1983), two former colleagues on the Yale Daily News and accomplished journalists in New Haven. The Basses have long served as confidantes.  

Paul’s innovative online community newspaper, the New Haven Independent, was one of the first sites to link to this blog, and Carole blogged for the Yale Alumni Magazine about my definitive exit from the HD closet in 2012.

I welled with emotion at seeing my old friends, hearing good news about their lives and young adult daughters, and sharing my joy at having remained asymptomatic beyond my mother’s age of onset.

Paul and Carole Bass (photo by Gene Veritas)

Supporters of the HD cause

That evening in New York I dined with another Yale friend, Norman Oder (class of 1983), and his girlfriend Maryanne. A journalist, editor, and founder of the watchdog blog Atlantic Yards/Pacific Park Report, Norman urged me to start this blog and has edited virtually every piece since its inception ten years ago.

During my 24 hours in New York, Norman and I had several deep conversations about my future health, the destiny of this blog, and numerous aspects of the HD movement. He is my “HD alter ego.”

On April 13, I had lunch with yet another classmate, Adam Glick, a businessman and philanthropist who has generously supported the HD cause. Adam’s real estate company owns the Parker Palm Springs, the hotel in Palm Springs, CA, that expertly hosts the annual, CHDI-sponsored HD Therapeutics Conference when it takes place in the U.S.

I gave Adam a rundown of the 2015 conference, which I attended. We also discussed the “nocebo effect,” the idea that the expectation of illness can bring on symptoms even though a person is not ill.

I told Adam that last year two major supplements – coenzyme Q10 and creatine – thought to have potential for treating HD were proven ineffective. I speculated that my belief in these supplements’ efficacy might have contributed to my lack of symptoms.

Quiet resolve

At Maryanne’s suggestion, I visited the Museum of Modern Art (MOMA) to view the special exhibition of Jacob Lawrence’s series of paintings about the great migration of African-Americans from the rural South to the urban North in the mid-20th century.

This significant event in our nation’s history is forgotten by many. As a professional historian, I was both intrigued and moved by the tempera paintings depicting the hardships of African-Americans in the South and the brave decision by millions to uproot themselves to find a better life.

My teenage daughter, a first-year high school student, had asked me to take photos of murals in New York. I didn’t have time to search for murals, but Lawrence’s paintings are mural-like and tell a vast story. I will soon show them to her.

Visiting MOMA gave me a break from the HD-laden aspects of my trip. Yet I could not help but draw a parallel between the quiet resolve of the migrants and the yearning of the HD community for liberation from the yoke of Huntington’s disease.

Through such resolve we can maintain the momentum necessary for defeating HD.

The African-American South-North migration of the mid-20th century as depicted in one of the paintings of Jacob Lawrence (photo by Gene Veritas)

(I wish to thank the individuals and organizations that organized the conference and sponsored my trip: Sue McGann, HDSA-CT, and the Wireless Zone Foundation.)

(Disclosure: I hold a symbolic amount of Isis Pharmaceuticals stock.)