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).
