In the quest for Huntington’s disease therapies, scientists have found key intellectual fuel for understanding the genetics of this fatal neurodegenerative disorder and developing therapies.
A brainstorming strategy became the trademark of the HD-focused Hereditary Disease Foundation (HDF), founded in 1974 by leading Los Angeles psychoanalyst and HD activist Milton Wexler as an offshoot of the Huntington’s Disease Society of America (HDSA).
Wexler organized multidisciplinary small workshops of scientists aimed at spontaneous discussion – as opposed to dry scientific presentations with slides – to search for the HD gene and develop treatments (click here to read more).
Allan Tobin, Ph.D., the former director of the Brain Research Institute at the University of California, Los Angeles (UCLA), ran hundreds of workshops for the HDF and later for CHDI Foundation, Inc. (CHDI), today the main private funder of HD therapeutic research.
Involving the affected
Many scientists have had little or no contact with HD families, so the HDF has included individuals from those families in its workshops. I was exposed to this approach in 2012, when Dr. Tobin transformed my desire to simply blog about a CHDI workshop into an event that included a 90-minute discussion of HD’s health and social ramifications based on my family’s story.
On the morning of January 30, I once again interacted with HD scientists, answering an invitation from HDF CEO Meghan Donaldson to offer my “perspective as both a family member and someone who is gene-positive,” aiming to help connect researchers “to the patients and the disease and to strengthen their resolve for finding a treatment.”
I not only spoke about my HD journey but also exchanged ideas with the scientists about their mission of developing therapies and also the many challenges faced by the HD community.
For me, exploring science with researchers serves as both mental enrichment and coping mechanism as I strive to forestall what research predicts will be my inevitable HD onset. Of course, I hoped to contribute to the scientific mission.
At the workshop: seated,
from left to right, Mahmoud Pouladi, M.Sc., Ph.D., Osama Al Dalahmah, M.D.,
Ph.D., Ashley Robbins, Gene Veritas (aka Kenneth P. Serbin), Sarah Hernandez, Ph.D.,
William Yang, M.D., Ph.D. Standing,
from left to right, Xinhong Chen, Andrew Yoo, Ph.D., Anton Reiner, Ph.D.,
Baljit Khakh, Ph.D., Nicole Calakos, M.D., Ph.D., Ed Lein, Ph.D., Beverly
Davidson, Ph.D., Nathaniel Heintz, Ph.D., Harry Orr, Ph.D., Leslie Thompson,
Ph.D., Myriam Heiman, Ph.D., Shawn Davidson, Ph.D., Steven Finkbeiner, M.D.,
Ph.D., Roy Maimon, Ph.D. (photo by Julie Porter, HDF) (Click on the image to enlarge it.)
Pondering modifier genes and a proactive approach
My 80-minute encounter with 20 scientists kicked off the two-day HDF Milton Wexler Interdisciplinary Workshop, held at the Huntley Hotel in Santa Monica, CA.
To provide background, before the meeting HDF Director of Research Programs Sarah Hernandez, Ph.D., sent the participants a copy of my article “Striving for a Realistic and Unapologetic View of Huntington’s Disease” from the Journal of Huntington’s Disease.
With the HDF’s permission, I recorded my remarks and Q & A with the scientists. As is customary, the confidential, scientific portion of the workshop was not recorded, to encourage uninhibited brainstorming.
After Dr. Sarah Hernandez introduced me, I gave an overview of my family’s fight against HD, including my mother’s diagnosis with the disorder in 1995, the genetic test revealing my risk in 1999, my gradual exit from the “terrible and lonely HD closet,” and strategies for delaying onset.
I discussed the possible key role of modifier genes in enabling me to reach the age of 64 still fully functioning – in contrast with my mother, whose symptoms began in her late 40s, ending with her death at the age of 68 (click here to read more).
Just before the meeting, I had discussed with two of the scientists that “maybe I should get my genome sequenced and find out if I actually have any of those modifier genes,” I told the scientists.
I noted, however, that no routine genetic tests exist for these genes and that establishing them might “open a whole new Pandora's box of bioethical considerations,” given the potential for unsettling messages. We'd have to have new protocols.”
“So, yes, I think it might be good to have those tests, but we've got to think very carefully about jumping into that,” I said. “But maybe for science, I could do my own whole genome sequence and write a blog article about it and analyze my modifier genes.”
I stressed that a “proactive approach is absolutely essential.” That option was unavailable to my mother, the first person to develop HD in an extended family with no knowledge of the disease.
Seeking to manage HD
The scientists probed various facets of my family’s HD experience and my advocacy.
I explained the importance of the HDSA-San Diego support group in providing vital information about such matters as genetic testing and obtaining long-term care insurance. I also discussed my timeline for testing and how I did so anonymously. I reflected on how my colleagues at the University of San Diego reacted positively to my exit from the closet and the full-throated advocacy that I could now pursue.
The concerns about discrimination led me to underscore the importance of the Affordable Care Act and the Genetic Information Nondiscrimination Act in eliminating discrimination against those with preexisting conditions.
Some wanted to know about the very difficult social and psychological challenges involved in genetic testing, and how to convince those worried about HD to reach out to medical professionals.
Given how devastating the discovery of HD in a family can be, I advocated a “gentle” and gradual approach to getting people involved, recalling that research studies such as Enroll-HD allow people to participate anonymously and without knowing their genetic test results.
I pointed out that, despite the fear and devastation associated with HD, today the HD community has real hopes for clinical trials of HD-specific remedies. Such hope did not exist a quarter-century ago. As I tell younger people just starting their struggle against HD, although “there may not be the magic bullet,” HD might ultimately be “managed like other diseases are managed like heart disease, diabetes, and HIV.”
Involving presymptomatic people in trials
I was both humbled and thrilled that the scientists wanted my observations on various aspects of the search for therapies.
In my opening remarks, I had stated that, in comparison with the start of my HD journey in the late 1990s, thankfully it has been harder for me to track the progress because of so many research and clinical trial programs. In her introduction, Dr. Hernandez noted that I am at work on a biosocial history of the HD movement.
UCLA neuroscientist Baljit Khakh, Ph.D., asked whether I could identify “errors” to be avoided or “strengths” to be reproduced, as well as trends worth noting.
In response, I expressed my frustration about the lack of opportunity for presymptomatic gene carriers like me to participate in clinical trials. The now defunct Triplet Therapeutics, Inc., had planned such a trial, I observed, and that the Alzheimer’s disease field has had such a trial.
“We're a valuable resource,” I said, recognizing that such trials require approval by the U.S. Food and Drug Administration and also involve bioethical and financial considerations.
However, I also observed that “the field's done a great job of trying to diversify [drug] targets,” because of the many types of approaches under research.
Addressing the cognitive deficit
Nathaniel Heintz, Ph.D., of The Rockefeller University asked about the importance of clinical trials to test drugs to treat just symptoms, without modifying the course of the disease. Treatments developed for other diseases, like Parkinson’s, benefit millions, he noted, but does HD as a rare disease face a greater challenge to attract trial volunteers?
I observed that HD now has three treatments for chorea,
the involuntary, dancelike movements experienced by many of the affected.
However, I also pointed out that HD clinical trials are very U.S.- and Europe-based, avoiding important countries such as Brazil, which was not included in Enroll-HD. I observed how HD families in Brazil and other parts of the world are “desperate to participate in clinical trials.”
Xinhong Chen, a lab researchers at the California Institute of Technology, touched on another facet of Dr. Heintz’s question: what symptoms do people most want treated to improve their quality of life?
I pointed to the importance of reducing the “cognitive deficit” that occurs with HD and prevents people from engaging in daily functions, caring for themselves, and communicating with others. I added that I had hoped to take pridopidine, a pill developed for this purpose. Sadly, the pridopidine trial failed in April 2023.
Andrew Yoo, Ph.D., of Washington University in St. Louis, wanted to know how to overcome the lack of interest in HD and related research in his native South Korea.
The leadership of the HDF, CHDI, HDSA, and the Huntington Study Group (HSG) should push for greater “diversity” on the international level, I said, suggesting that the HSG could send a delegation to South Korea. Also, advocates and medical personnel can spur action on HD, Alzheimer’s, and other neurodegenerative diseases by alerting people to the caregiving crisis, which is global, I observed.
The scientists get down to business
I was energized by my exchange with the scientists.
After my session, the workshop participants took up the main business of the rest of that day and the next: “cell type specific biology in Huntington’s disease.”
That activity was chaired by William Yang, M.D., Ph.D., of UCLA, Myriam Heiman, Ph.D., of the Massachusetts Institute of Technology, and Steven Finkbeiner, M.D., Ph.D., of the University of California, San Francisco.
Through their brainstorming – the first session of which I observed – the participants aimed to advance ideas for HD therapies.
On January 29, I lunched with Dr. Yang, gave a slide presentation on my advocacy to his research team, and toured his lab. I also interviewed Dr. Yang on his latest research.
Stay tuned for my next article: Dr. Yang’s long interest in HD and his enthusiastic outlook for potential therapies.
Disclosure: the Hereditary Disease Foundation covered my workshop travel expenses.
Gene Veritas (left) with Dr. William Yang in his UCLA office. In the background: a medium spiny neuron, one of the brain cells most affected by Huntington’s disease (photo Nan Wang, Ph.D., of the Yang Research Group).
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