“The symposium in Sacramento was the best HD [Huntington’s disease] gathering we have ever attended,” Bob Lohse wrote for his wife, Gail, who has HD. “We expected lunch sandwiches and sodas and were blown away with the spread. Your organization was a mix of progress, ‘fun,’ and Q/A with speakers available for questions during breaks. We thought Kyle [Fink] did a great job of explaining how all this gene/DNA stuff ties together for someone not a DNA engineer.”
Dr. Kyle Fink, from UC Davis, was one of seven keynote speakers who presented hope and understanding to attendees at Help 4 HD International’s third annual symposium on April 9, 2016, in Sacramento, California. In addition to speakers’ presentations, the symposium featured hands-on activities, a silent auction to raise money for JHD (Juvenile Huntington’s disease) research, and recognition of some very special people in the HD community.
Dr. Jan Nolta, “Bench to Bedside”
After opening remarks by Katie Jackson (president) and Katrina Hamel (vice president), Dr. Jan Nolta, Director of the UC Davis Stem Cell Program and Institute for Regenerative Cures, opened the day’s presentations with “Bench to Bedside,” a talk about PRE-CELL, her stem cell research that she hopes will produce a therapy for HD. PRE-CELL is funded by CIRM (California Institute of Regenerative Medicine), and Nolta’s team has applied for bridging funds for additional short-term studies that the FDA (Food and Drug Administration) has requested before approving human clinical trials.
Nolta’s lab is focusing on producing “paramedic” mesenchymal (MSC) stem cells that will deliver Brain Derived Neurotrophic Factor (BDNF) to the brain. BDNF is very low in people with HD, and so the paramedic cells, which are mature cells derived from healthy bone marrow donors, are engineered to deliver BDNF to the brain. The goal of the research, said Nolta, is to “slow down striatal degeneration and hopefully coax the new striatal neurons to replace those that are dying.” Nolta noted that in her research, they’ve been able to measure in the HD mice that receive BDNF a reduction in anxiety, a regeneration of striatal volume, and a 15 percent increase in lifespan.
In October, the FDA required that Nolta’s team try the therapy in pigs, so they are looking for additional funding to purchase the pigs and are hoping they will then be ready to move into HD-CELL, the human clinical trials later this year. According to Dr. Nolta’s website (www.jannolta.com), her team is seeking an industry partner to help take the MSC/BDNF platform to even more patients, outside of their planned initial Phase 1 clinical trial.
Jimmy Pollard, “You Are a Part of the Change”
Jimmy Pollard, a popular speaker for CHDI who lives in Lowell, Massachusetts, opened his morning presentation with the theme of “Families Keep Telling Their Stories.” His brief history of HD began in East Hampton, New York, where a young doctor named George Huntington saw families with this “curiosity” and continued to Oklahoma in 1888, where Nora Ball and Charly Guthrie had four kids, one of whom was famed singer-songwriter Woody Guthrie. Nora Guthrie developed HD, and Woody moved to Brooklyn, where he married dancer Marjorie. As Woody developed symptoms of HD, Marjorie began to tell her story. Doctors told her to find other families, so she put an ad in the newspaper, found other families who were living with HD, and founded CCHD, the Committee to Combat Huntington’s Disease, which is now known as HDSA, or Huntington’s Disease Society of America.
Pollard said, “Families told stories, organized, partnered up with doctors and researchers, and now we have pharmaceutical and biotech companies interested in HD.”
He noted that Marjorie always talked about the ripple effect of the pebble being tossed into the pond and said that’s what happened and continues to happen in the HD community because, “Families keep telling their stories.” Without those stories, he said, there would be no change. Equally important, according to Pollard, is that families continue to participate in clinical trials.
Participant Lisa Mooney said, “I loved Jimmy Pollard’s presentation. It was such a thoughtful addition to celebrate families moving science forward with participation in studies.”
Morning Panel: “Update on Clinical Trials and Studies in HD”
After a short break, a three-person panel presented updates on the progress of current clinical trials and studies. Dr. Ben Cadieux, Senior Director of Clinical Development at Raptor Pharmaceuticals; Dr. Victor Abler, neurologist and Global Medical Director of Teva Pharmaceuticals; and Dr. Peg Nopoulos, professor of psychiatry and pediatric neurology at the University of Iowa shared research and results with an audience that ranged from scientists and medical professionals to HD patients and their caregivers.
First up, Abler talked about three drugs that Teva currently has in the pipeline. The first clinical trial he spoke of is Pride-HD, a Phase 2 clinical study of pridopidine to see what effect it has on movement, thinking, and behavior, compared to placebo, in people with HD after 26 weeks of use, one tablet per day. Abler pointed out that it is not for chorea, but is for other physical motor symptoms. Researchers believe that the drug may have an effect on some of the symptoms of HD that depend on dopamine. He also spoke about the Legato-HD trial, which seeks to measure the effects of laquinimod, an immunomodulator that has already been in clinical trials for multiple sclerosis. Legato-HD is currently enrolling and is for people with little or no motor symptoms. The third study, SD-809, often referred to as “the next generation” of tetrabenazine, is currently waiting for FDA approval for the treatment of chorea. According to Teva’s website, SD-809, or deutetrabenazine, reduces dystonia as well as chorea and has fewer side effects than tetrabenazine.
Cadieux spoke about Raptor’s drug RP103, a cysteamine bitartrate that was approved for another disease (cystinosis), not HD, but is believed to be a potential drug therapy for HD. Cadieux explained that the drug has antioxidant properties and that HD mice improve motor symptoms and survive longer when placed on RP103. He said patients are currently enrolled in long-term trials in France. Using the total motor scale for HD to measure the effectiveness of the drug, those receiving early treatment do 25 percent better than those receiving later treatment, and completers who are on the drug for a total of 36 months do 35 percent better than non-completers. He said they are currently developing Phase 3, a multinational clinical trial in which they hope to include patients in the U.S., something that Huntington Study Group (HSG) is working on with the FDA. Raptor’s website says that, “The potential clinical benefit of RP103 in Huntington’s disease is reinforced by preclinical studies supporting three proposed mechanisms of action: 1) increased synthesis and mobilization of cysteine resulting in increased levels of glutathione and reduced oxidative stress, 2) inhibition of transglutaminase and induction of a heat shock protein (HSP) response, which assists in promoting proper protein folding and reduced proteolysis, and 3) enhanced gene transcription and increased expression and secretion of brain-derived neurotrophic factor (BDNF).”
Nopoulos, who is the director of Kids-HD and Kids-JHD studies at the University of Iowa, shared some of the goals and findings of her research. She said that brain development in humans continues through the age of 25, and in Kids-HD, they are trying to determine if there may be subtle signs of HD even in childhood. Thus far, research has shown that the higher the CAG repeat, the lower the striatum development, and so the cerebellum compensates by enlarging; however, with CAG repeats between 45 and 59, there are subtle symptoms in childhood because the cerebellum is not quite compensating. Nopoulos said that Htt (the Huntingtin gene) appears to be evolutionary because the more repeats, the better the brain development as evidenced by a higher IQ and a bigger brain. Nopoulos’s studies are funded by grants that pay all travel costs for the family of a child participating in either study, plus there is monetary compensation for the child. As a caveat, she added, “Kids have to want to do it and to understand about HD and that they’re at risk.”
Nopoulos noted that the DeNovo study has shown that a CAG repeat of 30+ is more unstable, particularly in males, and that in rare cases, their kids can develop HD.
Several attendees noted that it was good to hear about the programs at University of Iowa because they really didn’t know much about JHD research.
Dr. Vicki Wheelock, “Pre-Cell: The Path Forward and Findings Along the Way”
Wheelock, director of the UC Davis Center of Excellence, talked about Pre-Cell, an observational study at UC Davis that is managed by Terry Tempkin, ARNP. The trial to develop “the best therapy possible” began five years ago and studies adults at six-month intervals. Wheelock said 42 patients were screened, and 32 were admitted to the trial which includes a study of behavior and movement, brain imaging, and biomarkers.
Wheelock said the MRIs have shown slow, subtle changes, and the Unified HD Rating Scale has shown a slow progression in members of the trial. The trial also identifies problem behaviors, does an E-Cog rating, and measures quality of life. Spinal fluid that’s drawn is sent to Mass General for analysis and has shown plasma BDNF to be very low.
“We have developed measurement tools to be shared with the world,” said Wheelock. “Good science takes time.”
Dr. Kyle Fink, “Gene Therapy in JHD”
Fink, who is part of Nolta’s lab at UC Davis, explained his research that he hopes will lead to clinical trials for Juvenile Huntington’s disease. He’s working on gene modification or correction, targeting the DNA that is the root of the disease. His research with JHD mice has shown the CAG repeat to collapse down to approximately 16 CAG repeats and has produced mutant gene silencing.
Fink said his study is looking for the best way to deliver the therapy to the DNA. “Htt [the huntingin gene] is expressed throughout the body,” said Fink, “so where does it [the therapy] need to be delivered?”
They’re not sure yet what will happen if one area is treated and not another. Fink added, “Htt is critical for development, so the embryo won’t make it out of utero with a total absence of Htt.”
He said that JHD research may help scientists understand how other genes affect the development of the disease, but, he emphasized, “The bottom line is that we need funding to continue.”
Dr. Peg Nopoulos, “The Neuropsychiatric Disorder”
In addition to directing the Kids-HD and Kids-JHD studies at the University of Iowa, Nopoulos is a psychiatrist. She explained, with the use of slides, that the striatum (a part of the brain known to be affected by HD) is highly connected to the frontal lobe; thus, non-motor symptoms controlled by the frontal lobe often appear years before motor symptoms appear. She explained that while psychiatric and cognitive symptoms are the most disruptive for individuals and for families, they are also highly treatable.
Nopoulos pointed out that depressive symptoms decrease as the disease progresses, and are probably more situational than organic. According to Nopoulos, research has shown that major depressive syndrome has about the same prevalence in the HD population as in the non-HD population.
“The suicide rate,” said Nopoulos, “is higher right before (23.5 percent) and right after (21 percent) diagnosis.”
Nopoulos explained that the striatum helps control frontal lobe symptoms, so impairment of the striatum increases frontal symptoms. An increase in agitation and irritability are probably the most common and often contributes to the difficulty of getting placement into and retention in a care facility. Other problematic frontal lobe symptoms include impulsivity and disinhibition, a lack of insight and unawareness (anosognosia), and apathy.
“Apathy,” said Nopoulos, “is more common than depression and, unlike depression, progresses with the disease. The world becomes very small, and the person with HD becomes isolated.” Nopoulos pointed out that this is often more of an issue for the family than it is for the patient, urging that families and doctors ask the patient, “What is your quality of life?” If the patient is content with his/her quality of life, then the isolation is more of a problem for the family than for the patient.
Nopoulos also explained that the cerebellum is also very connected to the striatum and when affected causes increased chorea, difficulty with balance and swallowing, cognitive impairment, and an increase in psychiatric symptoms. Drugs that modulate the neurotransmitters change the brain chemistry: too much dopamine results in chorea, psychiatric symptoms, mainly agitation and irritability. Nopoulos pointed out that treatment of psychiatric symptoms is the same as treatment of psychiatric symptoms caused by other conditions, such as bipolar disorder and schizophrenia. She said the psychotherapy can be helpful in the early stages and encouraged consultation of The Physician’s Guide to the Management of Huntington’s Disease, published by HDSA.
Terry Tempkin, ARNP at UC Davis, Honored
An emotional tribute to Terry Tempkin, who is loved by many families who attend the clinic at UC Davis Center of Excellence, began with a video of colleagues saying their goodbyes as Tempkin prepares to retire. With barely a dry eye in the audience, Tempkin, who works with over 500 HD families, said, “It is about the families. It’s an extraordinary partnership.”
Judy Roberson, president of the Joseph P. Roberson Foundation, presented a certificate to Tempkin, noting that she is the ONLY privately funded ARNP. Roberson said Tempkin is “a visionary, energetic, has heart, and is compassionate.”
Tempkin, in accepting the award, said, “I can think of no higher calling than to come together to help other people.”
She noted that the clinic began with eight patients and today serves 500.
“I’m leaving UC Davis,” said Tempkin, “but I’m not leaving the HD community.” She challenged everyone to reach out to other parts of the world with far fewer resources.
Joseph P. Roberson Person of the Year Award
Judy Roberson began with Margaret Mead’s famous quote, “Never doubt that a small group of thoughtful, committed citizens can change the world. Indeed, it’s the only thing that ever has.”
Roberson said that when her brother-in-law Joe was diagnosed, there was no one in northern California who knew anything about HD. He started the foundation and contacted Dr. Ira Shoulson, with HSG (Huntington Study Group). Shoulson told Joe he needed to find eight people for HSG to open a Huntington’s Clinic. At that time, there were only two in California. Joe found eight people, a clinic was opened at UC Davis, and Dr. Vicki Wheelock became the director. Now, the clinic cares for 500 people with HD. Terry Tempkin came up with the idea to honor one person each year, someone who showed courage and strength in their battle with HD.
Laura Gagnon, announced Roberson, was chosen as this year’s honoree. Gagnon, who lives in Woodland, California, and is a patient at UC Davis, is active in studies and trials and is the third person in her family to receive the award. She was a registered nurse for 40 years in maternity and lost her dad and brother to HD.
In surveys collected at the end of the symposium, one person answered the question, “What could be improved upon?” with this comment: “Nothing, except for a box of tissues on each table!”
Jimmy Pollard, “Hurry Up and Wait”
The afternoon closed with Jimmy Pollard teaching the audience what it feels like to live with HD, what it feels like to think with HD. Through hands-on activities and the use of volunteers, Pollard demonstrated what it’s like to experience slow thinking, the difference between recognition and recall, the difficulty trying to focus when there’s distraction, the difficulty in trying to plan, organize, and sequence, and the problem with impulsivity—“I can’t wait!”
As the audience tried to write their names ever-so-slowly, Pollard noted that fluency decreases, distractibility increases, and the “inner cheerleader” disappears. These things, he said, are the “seeds of misbehavior.”
In an exercise of trying to draw from memory the picture on the face of a penny, Pollard demonstrated the difference between recognition and recall. Recall, he pointed out, is a much more difficult task than recognition.
Through use of the Stroup Test (color names are printed in different colors; i.e., the word “red” might be printed in green, and the person must read the name rather than saying the color), Pollard demonstrated what happens when there’s cognitive interruption.
Finally, Pollard blindfolded a volunteer, turned her round and round, then asked her to find her way across the room to a designated spot, then asked another volunteer to count backwards from 100 by sevens. Both exercises demonstrated the frustration that occurs when there’s difficulty in organizing and planning.
“When skills start to erode,” said Pollard, “you just want to do things; others get judgmental, saying things like, ‘He could do it if he wanted to.’” But as tasks begin to take extra concentration, it becomes fatiguing, and people with HD just don’t want to continue. It takes more effort to recall, to answer hundreds of questions in a day, and it just becomes harder to stay focused.
One survey respondent commented, “I loved Jimmy Pollard because of his delivery style.”
Wrapping It Up
End-of-symposium evaluations reflected excitement about the day’s events: “I enjoyed the interactions between clinicians, scientists, patients, care partners, industry. The set-up of the meeting was conducive to a more intimate dialogue!”
As one respondent summed it up, “I enjoyed the talks, but I especially enjoyed the level of professionalism. From the appearance of the speakers and the coordinators to the wonderful food, it let me know that HDers are cared for and important and valuable.”