On April 9th, HOPESters Natty and Caitlin attended Help4HD’s 3rd annual symposium in Sacramento, California. The all-day event featured a wide range of presentations from speakers representing academic institutions, pharmaceutical companies, and research groups. The event honored the work and retirement of Terry Tempkin, RNC, MSN, ANP. Terry is the Nurse Practitioner at the HDSA Center of Excellence, University of California, Davis Medical Center, and Department of Neurology. The event was attended by HD families, researchers, and advocates and was a full day of education for all.
Sponsors of the event included Raptor Pharmaceuticals, The Griffin Foundation, Teva Neuroscience, Ionis Pharmaceuticals, and Lundbeck Pharmaceuticals. Attending the symposium allowed HOPESters the opportunity to meet with others in the HD community working for therapeutics, a cure, and better patient advocacy for those affected by Huntington’s disease (HD). Below is a summary of each presentation from the day.
Dr. Jan Nolta, Ph.D., Director of UC Davis Stem Cell Program and UC Davis Institute for Regenerative Cures and Dr. Vicki Wheelock, MD, Director of the UC Davis Huntington’s Disease Clinic
“Bench to Bedside; Mesenchymal Stem/Stromal cells Engineered to Produce Brain-Derived Neurotrophic Factor as a Potential Treatment for Huntington’s Disease”
“Pre-Cell: The Path Forward and Findings Along the Way”
Dr. Nolta and Dr. Wheelock presented current updates on UC Davis’s progress in its HD stem cell treatment clinical trial. The proposed treatment uses mesenchymal stem cells (MSCs) engineered by Dr. Nolta and others at UC Davis in order to overproduce brain-derived neurotrophic factor (BDNF) as a therapeutic for HD. In HD, medium spinal neurons of the striatum die out, resulting in many of the symptoms seen in HD patients. Current research has identified lowered levels of BDNF as a key cause of this cell death as the mutant huntingtin protein blocks production of BDNF at the RNA level and reduces axonal transport from cortical cells to the striatum.
MSCs have been developed as a viable candidate for delivery of BDNF into the striatum due to their reliable safety profile and ease to engineer. Mouse models of HD treated with implantation of these engineered MSCs have showed success in decreasing behavioral symptoms such as anxiety and reduced striatal atrophy. Mouse models have also revealed key information about the effectiveness of different dosages of MSC-delivered BDNF. Mouse model studies also showed an extended life span and increased neurogenesis, or production of new neurons, in mice treated with MSC-delivered BDNF. Please see this HOPES article on the UC Davis team’s research. The group at UC Davis has completed the first phase of their project plan, “Pre-Cell”, and are working to prove that delivery of MSCs can be done safely in larger mammals in order to receive approval for the first in-human trial of gene therapy engineered MSCs implanted into the brains of patients with Huntington’s disease. The most recent publication on this research is available here.
Jimmy Pollard, CHDI Foundation
“You Are a Part of the Change — Patient Participation in Clinical Trials”
Jimmy Pollard, HD health educator and advocate, spoke about the origins of Huntington’s disease, specifically with regards to its discovery by Dr. Huntington. However Jimmy spent the majority of his presentation taking about the value of HD families in accelerating research and education around HD. One example he gave was the advocacy work of Marjorie Guthrie when she discovered that her husband Woody Guthrie, renowned folk singer, was afflicted with HD. In addition to starting the Committee to Combat Huntington’s Disease, which eventually became the Huntington’s Disease Society of America, Marjorie Guthrie was also instrumental in the creation of the World Federation of Neurology’s Research Commission of Huntington’s chorea (as it was called at the time).
Jimmy also emphasized the value that sharing of stories, such as those in Life Interrupted, has for HD awareness efforts. Finally, he emphasized and thanked everyone in the room who had ever contributed to a clinical trial on HD, acknowledging the necessity and sacrifice of those who constantly supported research efforts.
Morning Panel: Update on Clinical Trials and Studies in HD
Dr. Victor Abler, Global Medical Director at Teva Pharmaceuticals
Dr. Abler described three current clinical trials that Teva Pharmaceuticals is conducting. The first is Pride-HD, which is a Phase II, double blind, randomized control trial testing the impact of pridopidine on motor impairment in patients with Huntington’s disease. Pride-HD is primarily aimed at testing the safety and efficacy of pridopidine at different dosages compared to placebo controls. This study is closed for enrollment but continuing through September of 2016.
The second trial presented was data from First-HD and ARC-HD, the former of which has been completed and the latter of which has completed enrollment but is still underway. These Phase III studies evaluated the safety and effectiveness of SD-809 (deutetrabenazine) in the treatment of chorea. Results have been positive with transition from tetrabenazine, the current treatment for chorea. The most common adverse side effects, affecting ≥5% of participants, were drowsiness, dry mouth, diarrhea, insomnia, and fatigue. SD-809 was granted Orphan Drug Designation for treatment of HD by the FDA in 2015.
The final trial presented was LEGATO-HD, a Phase II study to study the efficacy and safety of laquinimod in the treatment of HD. Laquinimod is understood to decrease inflammatory responses that occur in the brain of someone with HD. The primary endpoint for this study is measurement of a change from baseline in the Unified Huntington’s Disease Rating Scale- Total Motor Score (UHDRS-TMS) after 12 months of treatment. This study is currently enrolling.
Dr. Ben Cadieux, Senior Director of Clinical Development at Raptor Pharmaceuticals
Dr. Ben Cadieux discussed the investigation of RP-103 by Raptor Pharmaceuticals for the treatment of HD. The current Phase II/III trial is building on previous safety trials as well as findings that RP-103 is able to have effects on glucose metabolism, oxidative stress, and brain-derived neurotropic factor (BDNF) production, all of which are abnormal in the brains of those with HD. Measurements of effectiveness on the UHDRS-TFC and Independence Scale showed mild improvements over time in those taking RP-103 compared to controls. Following this Phase II/III trial, the next steps for Raptor are to continue analyzing the data for effectiveness and long-term safety and to develop a stage III protocol.
Dr. Peg Nopoulus, Professor of Psychiatry, Pediatrics, and Neurology at The University of Iowa, Kids HD and Kids JHD Research Director
Dr. Nopoulus presented her team’s work on the Kids HD and Kids JHD programs. The Kids HD study is a longitudinal study of children, adolescents, and young adults who are at-risk for HD. The goal of this research is to identify early changes in brain structure and development in those that are gene-expanded (GE) and will eventually develop HD compared to their gene non-expanded (GNE) counterparts in the at-risk population. In order to study brain structure and development changes, researchers measure brain structure and function as well as behavioral, motor, and cognitive abilities over time. To separate out the control, or NGE, individuals, researchers also conduct genetic testing of patients to determine their HD gene status, but due to the ethical implications of such information about minors, all information is deidentified.
Results thus far have shown reduced striatal volumes in those individuals that are gene-expanded in comparison to those that are gene non-expanded. As a longitudinal study, Kids-HD is still recruiting and is based out of the University of Iowa.
The Kids-JHD study overlaps with the Kids-HD study in most measurement endpoints, including brain volumes, cognitive and motor abilities. However, due to the current lack of significant research on JHD, Kids-JHD also aims to better understand the brain changes that occur in juvenile-onset, as opposed to adult-onset, of HD. In addition, the Kids-JHD program includes an extra day of clinical assessment conducted by a team of doctors who are experts in JHD. The team is able to assess, and if needed, make recommendations to parents and other physicians for the care of individuals with JHD. Reports with relevant information on the child’s clinical status and abilities are sent to local doctors and schools to help inform those involved in the child’s care and development.
Please see clinicaltrials.gov or this HDSA resource to find up to date information on clinical trials.
Kyle Fink, Ph.D. Post-Doctoral Fellow at the UC Davis Institute for Regenerative
Gene Therapy in JHD
Dr. Fink presented his research on the potential for gene modification using transcription-like effectors (TALES) as a treatment for JHD. The idea behind this research is to get to the root of the problem, the expanded CAG repeats in the Huntingtin gene, that result in production of mutant protein in those with HD. Targeting protein levels is an option but that would require the continuous administration of a drug to keep huntingtin protein levels low. Dr. Fink’s work uses TALES to target single-nucleotide polymorphisms (SNPs), or specific targets in the DNA and cause collapse of the CAG repeat extension or repression of the mutant gene. The collapse model works by using two TALES that target unique SNPS around the CAG repeat extension and cause shortening of the DNA until they reach a certain distance from each other (approximately 16-18 CAG repeats), and are no longer able to function. This results in a mutant HTT gene being shortened to one that has a normal CAG repeat length. TALES can also be used for gene silencing, another approach being investigated. When these TALES are used in patient fibroblasts (skin cells), researchers found a markedly reduced amount of mutant huntingtin protein. They also found a 20% reduction in the amount of RNA production, the precursor to the huntingtin protein. These experiments were also done in primary neuron cultures of transgenic mice, with similar results.
The main limitation to complete silencing or shortening of the mutant HTT gene seem to be delivery into the cells. Current research efforts and collaborations are focused on the development of various delivery options, including viral vectors, synthetic nanoparticles, or mesenchymal stem cells. This research is still in early stages, working in vitro with human cells and mice, but researchers hope to be able to progress to treatment of the striatum and cerebellum of mice.
Dr. Peg Napolous, Professor of Psychiatry, Pediatrics, and Neurology at The University of Iowa, Kids HD and Kids JHD Research Director
Psychiatric Aspects of Huntington’s Disease
Dr. Napolous discussed the extended and varied presentation of psychiatric symptoms in individuals with Huntington’s disease. Extended information on this topic is available here. Dr. Napolous emphasized the importance of understanding psychiatric and behavioral symptoms of HD because they typically appear years before motor symptoms do and early identification is important for the care of an individual both emotionally and medically. In addition, many of the psychiatric and behavioral symptoms are treatable with medications used for other disorders. Treatments for HD symptoms are not curative, but rather symptom management. For some aspects of the disease, such as cognitive abilities, apathy, and issues with balance, speech, and swallowing— currently available medications are minimally effective. However, for symptoms such as chorea, irritability, and depression, treatments can be very effective. Finally, Dr. Napolous emphasized the importance of having a team of care providers that can meet the unique needs of the HD patient and family.
Hurry Up and Wait
To conclude the conference, Jimmy Pollard engaged attendees with a presentation that worked to help build an understanding for the experience of HD. This session included an explanation of the ways in which thinking can be affected in those with HD, such as memory impairment, slower thinking, and difficulty focusing, organizing, and planning. One activity Jimmy had attendees do was to attempt to write their names at a rate of one letter every ten seconds and pay attention to the feelings that arose when they were not able to act more quickly. Participants described the task as frustrating, agitating, and tiring; they also noted that they were easily distracted when forced to move at such a pace. Another activity focused on HD patients’ typical dislike of surprises because of the increased difficulty it adds to their ability to plan. A participant was blindfolded and then told to find an item a few tables away. However, when she was close to her destination, Jimmy spun her around in several circles to cause disorientation. This ‘surprise’ of being spun around, was meant to mirror the way in which HD patients feel when something in their day is not the way the have come to expect it. Finally, Jimmy ended on one take home message, which was to “hurry up and wait”. A seemingly contradictory statement, Jimmy hoped to emphasize to attendees that the various cognitive effects of HD are complicated, and patients are often impatient with themselves and the world around them, especially when they are forced to function at a much slower pace than they want. As someone caring for, or interacting with, an individual with HD, it is important to be aware of their array of emotions and experiences and ‘hurry up’ when they need you to, but to ‘wait’ for them as well. Jimmy’s full presentation is available here.