The path to treating
Huntington’s disease – a potential major breakthrough in the history of science
and medicine – is becoming clearer.
That was the takeaway
message from the Ninth Annual HD Therapeutics Conference, organized by the CHDI Foundation, Inc. and held February 24-27 at the Parker hotel in Palm
Springs, CA. Spending tens of millions of dollars annually, CHDI is a non-profit, virtual biotech founded solely to
discover HD treatments. Some 300 participants from academia, the pharmaceutical industry, and biotech firms took part, as well as a number of patient advocates, including Olympic rowing medalist Sarah Winckless, who delivered the keynote address.
“The tagline would
have to be ‘it’s really getting real,’” said Robert Pacifici, Ph.D., the chief
scientific officer for CHDI Management, Inc., in an interview with me at the
conference. “What I’m seeing at this conference already is the culmination of
very large, very long-term efforts – things that have taken years and thousands
of person hours, patients’, caregivers’, researchers’, and physicians’ –
finally coming together in ways that are really conclusive and really helpful.”
All that work has
involved numerous questions about the disease and potential ways to treat it,
Dr. Pacifici explained.
“All of those things
sadly have an incredibly high attrition rate,” he observed. “The fact that we’re
getting answers is the thing that makes me the most excited. Sadly, sometimes
we don’t like the answer. Sometimes the answer is: ‘That doesn’t work.’ But
that’s still very useful for researchers.”
Winnowing out the
useless approaches allows researchers to “refocus our resources on something
that we feel has a better chance of bearing fruit,” Dr. Pacifici said.
Sitting one evening with
a group of CHDI researchers, I expressed the natural concern of the HD
community – a concern sometimes tinged with impatience and frustration: could
the rapidly expanding knowledge about HD result in an endless search for
treatments fueled by questions that simply produce new questions rather than
treatments?
They answered with an
emphatic no. Echoing Dr. Pacifici, they said that real solutions were in the works.
The conference did
seem more coherent in comparison with the previous three I had attended.
Indeed, as one senior CHDI advisor observed in response to my observation,
Huntington’s researchers now have an understandable “story to tell” about the
disease and the research.
You can watch my
interview with Dr. Pacifici in the video below. Just below the Pacifici interview, Portuguese speakers can watch my interview about the conference with Dr. Mônica Haddad of Brazil.
'It's Really Getting Real': Payoffs in the Effort to Treat Huntington's Disease from Gene Veritas on Vimeo.
A esperança de tratar a doença de Huntington: Dra. Mônica Haddad fala sobre a conferência da CHDI from Gene Veritas on Vimeo.
Confirming the shots on goal
Just three days
before the conference, CHDI and Genzyme Corporation announced an agreement to
jointly develop a “novel gene-silencing therapeutic for Huntington’s disease” using an adeno-associated virus, which does not cause disease, as a delivery system.
The venture expands
CHDI and other research projects’ portfolio of potential treatments for HD,
several of which are in the early stages of clinical trials or aim to begin
trials soon.
In Dr. Pacifici’s words,
the growing number of drug targets means there are more “shots on goal” in the
quest for treatments.
CHDI is concentrating
on “validating” (confirming) the targets to assure that as many potential
remedies as possible have a chance of becoming effective, safe treatments, Dr.
Pacifici explained.
“It’s important for
any drug discovery organization, because when you select a target, that’s what
underpins the rest of the (drug discovery) activity,” he said.
No organization has
yet discovered how to validate targets “exactly,” he said. However, CHDI is
especially working hard to insure that a “particular target is really tethered”
to the HD disease process and not some other disease or process, he added.
“While nobody has the
magic bullet there, it was really impressive to see the variety of approaches
that were taken,” Dr. Pacifici said of the talks on target validation.
These included X.
William Yang’s report on his latest research with transgenic HD mice, Ernest
Fraenkel’s study of the impact of the mutant huntingtin gene at the molecular
level, and CHDI scientist Jim Rosinski’s efforts to unify and interpret the
totality of biological data on HD by employing a systems biology approach.
You can watch an
excerpt from Dr. Fraenkel’s presentation, Dr. Rosinski’s full presentation, and
most of the other talks by viewing my 2014 CHDI video album.
Finding a modifier gene, delaying onset
Jim Gusella, Ph.D.,
one of the lead discoverers of the HD gene in 1993, described the work of a
large international team to find a so-called modifier gene, which might act as
a trigger for the disease and affect the rate of progression.
Such a gene could
also become the target of a treatment, Dr. Pacifici explained.
“Imagine coming up
with a drug that can delay your age of onset by 30 years,” he said, referring
to the wide variability in age of onset for people with the same degree of
mutation. “That would be fabulous.”
The Gusella team’s
search for the modifier gene points to “a couple of specific sites on human
chromosomes,” Dr. Pacifici said. In contrast with the numerous studies done in
mice and other organisms, this project “was generated with human data. So we
don’t have to worry about the predictive value of those studies.”
Dr. Pacifici
described the 20-year quest for the modifier gene as “a great example of how
the community pulls together and the generosity of the families affects the
progress of research. Without your blood, without your DNA sequences, without
your permission, there’s no way these types of studies could be done.”
The team analyzed DNA
from more than 4,000 HD gene carriers and affected individuals. The study also
required the ongoing commitment of participants to allow researchers to track
their symptoms.
“We need to make the
correlation as to when the motoric age of onset (the start of involuntary
movements) occurred,” Dr. Pacifici explained. “That’s invaluable and incredibly
appreciated. Hopefully now people can understand why participation in trials
like this leads to such exciting discoveries.”
New potential therapies
A session on “novel
therapeutic approaches” focused on potential remedies different from the
traditional concept of oral medication.
Jan Vesper, M.D., presented the promising results of his pilot trial using
deep brain stimulation, which involves the placement in the brain of metal
capsules covered with electrodes. Long-time HD specialist Gill Bates, Ph.D.,
discussed her new research on the muscle deterioration involved in HD mice and
the potential use of a myostatin inhibitor to remedy the problem as well as perhaps ameliorate the involuntary movements
typically suffered by patients. Beth
Stevens, Ph.D., explained the importance of restoring proper function of microglia
(cells performing as the immune system of the nervous system) in pruning
synapses, the connections between brain cells.
‘A horrible, lifelong case of jet lag’
Changes in people’s behavior
could provide another way to ameliorate HD, Dr. Pacifici noted.
Along those lines,
Christopher Colwell, Ph.D., presented critical new research on the circadian
rhythm – our sleep clocks – and how its disrupted function in HD might worsen
symptoms.
“Think of
Huntington’s almost as a horrible, lifelong case of jet lag,” Dr. Pacifici said
in describing the implications of Colwell’s and others’ work in this area. “By
entraining (synchronizing) the clocks in your mind and the clocks in your
various organs to stay in sync with each other – by using things like when you
eat, when you go to sleep, when you exercise, what kind of light you’re exposed
to – you could compensate for some of the mechanisms that go awry in
Huntington’s disease. That type of regimen could be a therapy, or an add-on to
a therapy, rather than something as traditional as a pill.”
Dr. Colwell’s engaging
talk provided a wealth of ideas about the circadian rhythm and keeping it
healthy. You can watch his presentation in the video below.
Circadian disruptions in Huntington's disease: mechanisms and possible treatment options from Gene Veritas on Vimeo.
Alpar Lazar, Ph.D., Stephen Morairty, Ph.D., and Tom
Warner, Ph.D., provided additional evidence about the importance of the sleep
cycle.
Assuring the drug does its job
In the session on
“huntingtin lowering biomarkers,” several presenters described cutting-edge
techniques for measuring the efficacy of potential therapies designed to attack
HD at its genetic roots and reduce the effects of the mutant huntingtin
protein. Those projects include the above-mentioned CHDI-Genzyme venture and
the Isis-Roche-CHDI partnership.
“What you’d like to
do is make sure that after you administer one of those drugs, that the drug has
done its job,” Dr. Pacifici explained. “We don’t want to wait for five years to measure hundreds of people
only to find out that the drug never did its primary job, which was to lower
huntingtin levels.”
Along with an expert
task force, CHDI has developed a series of ways to determine
huntingtin-lowering efficacy in humans within a period of weeks, he said.
“Because we want to
know what’s going on in the human brain, and we can’t go in there and take a
little chunk of brain out every couple of weeks, we have to figure out a way of
non-invasively making those measurements,” Dr. Pacifici
continued.
The techniques
include quantitative EEG (a kind of brain mapping), magnetic resonances pectroscopy, assessment of
dysfunction in the mitochondria (the powerhouses of the cell), and measurement
of huntingtin in bodily fluids such as cerebral spinal fluid.
Scientists are
developing ways to measure other types of potential HD remedies such as
phosphodiesterase inhibitors (aka “Viagra for the brain”).
As the HD field moves
towards clinical trials, CHDI has increasingly emphasized the need for the
exchange of information between scientists in the lab and physicians and others
focused on patients and clinical trials, Dr. Pacifici commented. Such teamwork
will enhance the possibility of finding treatments, he said.
Supporting Enroll-HD
The conference also
featured several activities promoting Enroll-HD.
First announced in 2010 and officially launched in 2012, the CHDI-sponsored
Enroll-HD is building a worldwide registry of HD
patients, HD gene carriers, untested at-risk individuals, family members, and
volunteers. It aims to facilitate scientific understanding of HD, identify
potential participants in clinical trials, and therefore speed the process of
finding therapies.
In a
pre-conference meeting of Enroll-HD physicians and administrators on February
23, participants focused on ways to use the project to improve patient care. On
February 24, Enroll-HD’s international steering committee met to discuss
administrative matters.
On February 25, the
CHDI conference featured a practical lunchtime session that provided an update
on program details like the number of participants.
A ‘matchmaker’ facilitating clinical trials
In order to deepen
understanding of Huntington’s, Enroll-HD looks at individual and family
histories of HD “over a long period of time,” Joe Giuliano, CHDI’s director of
clinical operations and the chief Enroll-HD administrator, said in an interview
on February 24.
“The vision for
Enroll-HD is to provide a clinical research platform that can be used by the
community of HD researchers around the world to do clinical studies, and it can
be used by pharmaceutical sponsors to do clinical trials,” Giuliano explained.
“It’s an enabling tool to help answer important questions about Huntington’s
disease using clinical research.”
Giuliano described the program’s three levels: the international
administration, the wide range of sites based in local communities (run by
physicians and other health workers), and the HD families.
“It starts with
families,” Giuliano said. “Enroll-HD
is really a study for all the family to participate in.
“Enroll-HD is a great
opportunity for us to come together as a global research community. The clinical trials that are going to lead ultimately to new
therapies for Huntington’s disease are going to be conducted in global clinical
trials…. The more people we can get in Enroll-HD, the more powerful the study
can become, for example, for recruiting for clinical trials. Enroll-HD can help
identify participants … who are eligible for clinical trials.”
This potential makes
Enroll-HD “very attractive” for pharmaceutical companies to collaborate with
the program, Giuliano said.
Enroll-HD is a
“matchmaker” putting together researchers, patients, drug companies, and
others, he continued.
Anybody in the HD
community can participate, including unaffected relatives of HD people. “By
joining Enroll-HD, you’re being very proactive in a lot of different ways,” he
said. “You’re providing the possibility that you may be eligible for a future
clinical trial.”
The larger the pool
of potential participants, the faster trials can take place, he concluded.
You can watch my
interview with Giuliano in the video below.
For other coverage of the conference, visit www.HDBuzz.net.
Coming soon: a
detailed report and more videos on Enroll-HD.
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