Adult stem cells designed to rescue
brain cells from death in Huntington’s disease patients could enter human
testing in the next three to four years, thanks to a $19 million grant to an HD
research team at the University of California, Davis (UC Davis), from the
California Institute for Regenerative Medicine (CIRM).
If successful, this first-ever stem cell
clinical trial for Huntington’s could pave the way for a possible treatment of
the devastating disorder.
At a public meeting July 26, the
oversight board of the $3 billion stem cell agency announced the award
to the lab of researcher Jan Nolta, Ph.D.,
a recognized specialist in mesenchymal (pronounced “meh-zen-KI-mal”) stem cells
(MSC), and her collaborator Vicki Wheelock, M.D., a neurologist and the
director of the Huntington’s Disease Society of America’s Center for Excellence
for Family Services and Research at UC Davis.
Dr. Nolta aims to introduce MSCs, which
act as natural “paramedics” in the body, into the brains of symptomatic HD
patients to test for safety and tolerability. The trial doses will be made from
a sample of MSCs extracted from a healthy donor.
MSCs produce a so-called “fertilizer for
the brain” (BDNF, brain-derived neurotrophic factor), whose levels
plummet drastically when someone has HD. Dr. Nolta and her team have engineered
MSCs to produce higher levels of BDNF in an attempt to help HD-damaged neurons
recover and avoid death, thus slowing, halting, or perhaps even reversing the
course of HD.
Dr. Nolta’s collaborator Gary Dunbar, Ph.D., of Central Michigan University, has already demonstrated that
these MSCs mostly stop symptoms in transgenic mice that have been given the
abnormal HD gene.
Dr. Jan Nolta (above) at the HD work bench at the Institute for Regenerative Cures. Below, Dr. Vicki Wheelock (photos by Gene Veritas).
The Nolta-Wheelock grant was one of
eight CIRM grants totaling $151 million to labs seeking treatments for
debilitating or fatal diseases, including Lou Gehrig’s disease, cancer, heart
disease, and spinal cord injuries. The awards were the second largest research
round in CIRM history. In 2009 the agency granted more than $200 million to
researchers.
With a score of 87/100, the
Nolta-Wheelock grant ranked highest in the state.
“We’re just so glad that we didn’t let
the community down,” Dr. Nolta told HD activist Melissa Biliardi on The HD View internet radio program on
July 23 in anticipation of the expected award.
In this same round UC Davis received two
other grants – to seek treatments for peripheral artery disease and osteoporosis
– that Dr. Nolta will help oversee in her role as the director of the UC Davis stem
cell program and the university’s Institute for Regenerative Cures (IRC), which
has nearly 150 affiliated faculty researchers.
“People are hopeful, truly hopeful for the first time,” Judy
Roberson, the former president of the Northern California Chapter of the
Huntington’s Disease Society of America (HDSA) and the widow of an HD victim,
said after the CIRM announcement. “This is a nightmarish, cruel disease in every way
but now, thanks to CIRM, we are turning the dream of a stem cell therapy trial
into a reality. Research means hope for people with this disease, but research
costs money. CIRM has given us all hope.”
The trial’s proposed timeline
CIRM will grant the $19 million over
four years, the proposed timeline of the clinical trial project. Most of the
money will cover charges such as surgeries, operating room and hospital costs,
MRI scans, and other items related to the actual trial.
According
to the proposal, the UC Davis team will spend the first year testing the safety
of MSCs in healthy non-human primates. This stage of the project will help the
team secure the necessary approval for human testing from the U.S. Food and
Drug Administration (FDA), which regulates clinical trials.
In
the project’s second year the team hopes to enroll at least 26 early-stage HD
patients in an observational study, including motor and psychiatric tests and
MRI brain scans, to obtain basic measurements of their health for comparison
with readings to be taken during the clinical trial.
At
the start of the third year, if all
regulatory approvals have been obtained as planned, the patients will
receive a single, direct injection of the MSCs into each side of their brains (a bilateral intrastriatal injection).
A special neurosurgical team, which will include experts from the University of
California, San Francisco, will bore a tiny hole into the skull to insert a
tiny cathether to deliver the cells. Direct insertion is necessary because of
the blood/brain barrier, which allows few medications to enter the brain.
Patients will have part of their heads shaved. However, their hair should grow back,
and the holes will heal over.
Half
of the patients will receive MSCs with the extra BDNF-producing capability,
while the other half will receive a placebo, MSCs without that capability.
Trial
participants will receive dosages in groups and on a staggered schedule, with
each successive group receiving a higher amount of the MSCs.
The
remainder of the trial will primarily check for the safety of the MSCs. As a
secondary goal, the scientists and physicians will also look for alleviation of
symptoms and evidence that the MSCs are improving the health of the brain.
This
first step in the trial is known as Phase I. If the MSCs prove safe, the team
would seek funding for Phases II and III to fully measure the cells’ efficacy.
All
of these plans must receive formal approval from UC Davis’s internal review
board and then the FDA, after which full details will become available for
potential trial participants.
A brief history of stem cells
To understand Dr. Nolta’s work we must
travel back in time to explore the roots of today’s revolution in stem cell
research.
Stem cells became a hot topic in the
first decade of the 21st century because of the controversy over one type:
embryonic stem cells. However, stem cell research long predates this
controversy.
Recall that a stem cell has a very
important property: it can make cells that eventually become another type of
cell such as a muscle cell, skin cell, or brain cell (neuron).
Stem cells help our bodies regenerate
lost or worn tissue and components such as our blood, liver, and skin.
Humans have understood the idea of
regeneration since ancient times, and scientists first started discussing the
concept of stem cells in the mid-1800s. Scientists first discovered stem cells
in mice bone marrow in the early 1960s.
The very first stem cell therapy
(treatment) in humans took place in 1968 with the successful bone marrow
transplant for a leukemia patient whose marrow donor was an identical twin.
This type of transplant helps the patient because bone marrow contains stem
cells that produce new blood cells. Because of stem cell research, other kinds
of transplantation and tissue regeneration have become possible.
Over the last few decades, scientists
have identified other types of stem cells, including those that produce
neurons. Stem cell research is now burgeoning around the world. Scientists use
stem cells both to understand human biology and to seek therapies for diseases
and traumas.
In August 2001, President George W. Bush
stopped federal funding for new embryonic stem cell research because of his
belief, shared by a good number of Americans, that such research destroyed
human life (the embryo from which the stem cells were taken) and was therefore
immoral. In California Bush’s restrictions spurred a successful movement to
pass a 2004 ballot initiative, Proposition 71, that skirted the president’s
order with state-level funding, created CIRM, and catapulted the state into
global leadership in stem cell research.
In recent years, however, new
discoveries have lessened the controversy about stem cells. Scientists have
made many advances using adult stem
cells – those extracted from a living human being without any risk. In 2006
researchers achieved another milestone that reduced the need for embryonic stem
cells: they could now take cells from the skin or other parts of the body and
reprogram them into a stem cell.
Dr. Alvin King of the University of California, Irvine, displays a neural stem cell on the screen of a microscope (photo by Gene Veritas).
The MSCs, Dr. Nolta’s focus for the past
25 years, are adult stem cells. Everyone has MSCs. They are found in the bone
marrow, as well as in fat, dental tissue, and the umbilical cord. They can make
bone, tendons, ligaments, and other connective tissues. MSCs grow well in lab
conditions, making them a prime candidate for research.
Along with other scientists, in recent
years Dr. Nolta and Leslie Thompson, Ph.D., of the University of California,
Irvine, another CIRM grantee, began employing stem cells in Huntington’s
research. Besides MSCs, HD researchers use human embryonic stem cells, human
induced pluripotent stem cells, neural stem cells, and others.
In Dr. Nolta’s assessment, MSCs appear
to have especially great potential in treating HD because of their abilities as
the body’s “paramedics.” This potential is described in detail below.
From child scientist to MSC expert
Dr. Nolta’s path to the potentially
historic MSC HD clinical trial began in childhood and took shape in the midst
of the stem cell revolution.
“I think I was probably born a
scientist,” she told me during a May 2011 visit to her lab on the occasion of
the HDSA Northern California Chapter’s annual convention. “I was the kid that
was out in the yard investigating bugs and watching eggs hatch and feeding baby
animals that were rescued and trying to understand how caterpillars went
through the chrysalis form and came out as moths and butterflies.”
Raised by a single working mom in the
small northern California town of Willows and depending on grants and
waitressing for her college education, Dr. Nolta received a degree in biology
from Sacramento State University in 1984.
After graduation Dr. Nolta took
M.A.-level science courses at UC Davis and volunteered in a lab. “We could take
stem cells from the bone marrow and culture them,” she recalled. “There was
this ‘magical’ potion that we could put them in and culture them for just a few
days and could watch them divide and grow into blood cells. I wanted to
secretly keep the cultures growing and study them.
“Where I fell in love with mesenchymal
stem cells was in 1987. We started doing long-term bone marrow cultures, and
there’s a component that grows out when you take a marrow aspirate from a human
being that’s a mono-layer of broad, flat cells.
We used to call those the marrow-stromal cells. They later got renamed to
mesenchymal stem cells due to their potentiality and all that they can do.”
Dr. Nolta learned that MSCs could assist
greatly in gene therapy. Also known as cellular therapy, gene therapy involves
the use or alteration of genes to treat disease. Dr. Nolta was impressed with
MSCs’ strong ability to assimilate and deliver gene therapy products.
“I realized very quickly that we could
engineer them to even better support the other cells in the body,” she
explained.
To deepen her knowledge of stem cells
and MSCs, Dr. Nolta enrolled in the Ph.D. program in molecular microbiology at
the University of Southern California under the mentorship of Dr. Donald Kohn, a specialist in pediatric bone marrow
transplantation. At Children’s Hospital Los Angeles she assisted in his
pioneering work on bubble baby syndrome, AIDS, and other conditions.
From this experience Dr. Nolta learned
the techniques of gene therapy, growing stem cells, and applying stem cell
therapies in the clinic. With Dr. Kohn’s team, she performed the first cord
blood gene therapy trial for infants born with bubble baby syndrome, a type of
serious immune deficiency.
In 2002 the Washington University School
of Medicine in St. Louis, one of the nation’s top medical schools, recruited
Dr. Nolta to help build its programs in gene therapy and stem cell research.
There she continued her work on gene therapy and MSCs and collaborated with her
close colleague Gerhard Bauer, Ph.D., in the establishment of a GMP (good
manufacturing practice) facility, a highly advanced lab crucial for producing cell
and gene therapies.
The
power of grassroots advocacy
However, the future of stem cell
research lay in California. In 2007 UC Davis lured Dr. Nolta back to her home
state to direct its stem cell programs under the umbrella of the brand-new IRC,
the Institute for Regenerative Cures. CIRM awarded UC Davis $21 million to
construct the IRC and its state-of-the art GMP facility. UC Davis contributed
$40 million to the project.
With little knowledge of Huntington’s
disease, Dr. Nolta had no plans to include it in her research program at the
IRC when she was recruited.
UC Davis stem cell program manager Geralyn Annett (left), HD patient Sharon Shaffer, Alexa Shaffer, and Dr. Nolta advocating for HD research at a CIRM board meeting at UC San Diego in 2008 (photo by Gene Veritas)
During her recruitment trip to UC Davis,
Dr. Nolta met Dr. Wheelock of the HDSA Center of Excellence.
“Have you ever considered using stem
cells to treat Huntington’s disease?” asked Dr. Wheelock as she rode with Dr.
Nolta in an elevator.
“You know, for the last 20 years, I have
been researching how to use stem cells to treat every part of the body except
the brain,” Dr. Nolta responded, citing the critical hurdle of the blood/brain
barrier.
“The families impacted by Huntington’s
disease are truly remarkable,” Dr. Wheelock rejoined. “I’d love to introduce
you to them.”
That conversation spurred Dr. Nolta to
take a scientific interest in HD. More importantly, meeting the families deeply
moved her. She decided to act.
With initial financial backing from HD advocates
from the Sacramento area and elsewhere, Dr. Nolta delved into a project to find
a way to use MSCs to combat HD.
Dr. Nolta used her early findings to
apply for a grant from CIRM. In 2009 the agency awarded her lab $2.7 million to
study the use of genetically reengineered MSCs to block HD at its genetic roots,
first in lab dishes, then in mice (explained below).
During our interview at the IRC, Dr.
Nolta pointed to the photographs of HD advocates on her desk.
“They change the course of what
scientists do,” she said, breaking into tears. “My life was forever changed.”
In all, local fundraising efforts have
provided some $100,000 for Dr. Nolta’s work. Donations have included $15,000
from the Deshalamar foundation and $40,000 from Team KJ, an Illinois initiative in support of Kara Jean
Fleming, a 40-year-old HD patient. The Joseph P. Roberson Foundation, named for the deceased husband of Judy Roberson,
has also supported Dr. Nolta’s work. Many other donors, large and small, have
also contributed.
Watching
the paramedics in action
With the new $19 million CIRM grant –
the largest in Dr. Nolta’s career – she and the UC Davis hope to set their MSC
research on the path to a treatment.
The MSCs’ many attributes make them
attractive for treating HD.
“They’re very social,” Dr. Nolta
explained as she played a highly magnified video in which the MSCs appeared to
swim and greet one another like people playing in a swimming pool. “They like
to interact with other cells.”
The MSCs also move around the body with
great facility, Dr. Nolta added. They can project little tubes, called
nanotubules, that tunnel into cells and inject them with necessary items such
as proteins and mitochondria, the powerhouses of the cell.
“It’s like giving a cell new batteries,”
Dr. Nolta explained. “They just open up a nanotubule and put the new component
into the other cell. So that’s why we call them paramedics. It’s like they’re
going around with tool kits to repair the other cells…. They like to check out
other cells, to see if they’re healthy. They can change what they produce from
what they sense from the environment and from the other cells. They just become
like little factories.”
“They almost look like living
organisms,” I observed.
“They are,” Dr. Nolta said. “They’re
alive.”
(Watch the video below to see the MSCs in action.)
The MSCs’ sociability results in part
from the fact that damaged or sick cells and neurons put out “distress signals”
that spur the paramedics into action, Dr. Nolta continued.
The same process occurs in the brain,
she added. In mice that carry the human Huntington’s gene and have HD-like
symptoms, MSCs injected into their brains migrated to the areas of damage.
Transplantations of human tissue often
trigger a rejection by the immune systems of the recipients, requiring them to
take anti-rejection drugs sometimes for the rest of their lives. This does not occur with MSCs, Dr. Nolta said.
“That’s the beauty of them,” she said.
“They’re transplanted from one patient to the next with really no regard to
tissue matching. They actually shelter themselves from the immune system
through some of the things that they secrete. We think that’s part of their
natural function in the body.
“When there’s a wound or a heart attack
or some kind of ischemic event, a stroke, they can go to that area, and they want
to cause the tissue to heal without scarring. That’s part of their innate
mission. They don’t want the immune system to see it while it’s getting fixed
up, because you could start making auto-antibodies to that damaged tissue, and
then you would destroy that tissue. We think that the MSC just go to the scene
of the injury and keep the immune system at bay while they’re doing their
remodeling. It’s kind of like keeping everybody out of a construction site.”
The
goal: restoring neurons and connections
According to Dr. Nolta, the MSCs secrete
substances that help restore the vital connections between neurons. Such
connections are lost in HD. Additionally, in secreting BDNF and other brain
growth factors, the MSCs can help damaged neurons recover. She likened this
scenario to a chain of Christmas lights that, missing a bulb, will go out.
Restoring the bulb – a healthy neuron – gets the whole chain working again.
In the case of the proposed clinical
trial, the UC Davis team will ramp up the MSCs’ capability to provide BDNF. In
mice tests, they have increased that capability by a hundredfold.
The big question, Dr. Nolta told me in
an interview on July 30, 2012, is this: how effective will MSCs prove in
helping the entire striatum, an area of the brain deeply compromised by HD and
where the MSCs will be injected?
“The MSCs can secrete huge amounts of
BDNF, so that might be effective” in helping to restore the striatum, she said.
Attacking
HD’s genetic roots
If the MSC BDNF trial proves successful,
the UC Davis team could use another up-and-coming tool for combatting HD: RNA
interference.
In designing a substance known as a
small interference RNA molecule (siRNA), other researchers have already reducedthe amount of harmful huntingtin protein in the brains of test animals.
A similar approach, known as antisense, has demonstrated similar results. Both approaches should enter
clinical trials within the next few years, if not sooner.
Still in the early stages of this aspect
of their research, Dr. Nolta and her UC Davis HD team have discovered a way to
deliver siRNA into cells in a dish using MSCs.
Some researchers are examining ways to
implant new neurons or fetal-striatal stem cells into patients’ brains to
repair the damage caused by HD. However, Dr. Nolta pointed out that those cells
could become affected by HD.
The use of siRNA could protect those and
other cells from HD. Dr. Nolta has photos and video of the MSC nanotubules
transferring siRNA into other cells. Her lab is now testing MSC siRNA in mice.
Controlling the huntingtin gene and
protein effectively is the “holy grail” of HD research because it would allow
gene-positive, non-symptomatic people like me to take a preventative treatment.
‘A
super, super clean place’
Although the human brain has MSCs, in HD
people those MSCs make the same mutant huntingtin as the other cells in the
brain and, indeed, in the rest of the body. Compromised in this manner, the
MSCs in HD people’s brains cannot make necessary levels of BDNF.
As a result, for the Phase I MSC BDNF
trial, the HD team will make batches of MSCs from bone marrow cells provided by
a healthy donor and therefore containing normal, non-disease-causing
huntingtin.
Federal regulations require GMP for any
substance that will be tested in humans. Thus, in the run-up to Phase I, the MSC
batches will be made at the UC Davis Institute for Regenerative Cure’s GMP
facility. It could make enough MSCs for 100 patients, Dr. Nolta said.
“You need your own facility to get up to
this scale,” she commented. “How to manufacture these batches of cells is a
whole industry in and of itself. It’s usually companies that would do this.
Sometimes they charge exorbitant fees.”
This level of “scale-up” to a clinical
trial is “our forte here,” Dr. Nolta told me in our recent interview. The
National Institutes of Health and insurance companies don’t fund these kinds of
initiatives, she noted, leading many drug candidates with good potential to
“fall into the valley of death.”
During my visit to the IRC, she referred
to the GMP as a “super, super clean place.” It will triple-check the quality of
the MSCs.
As explained to me by GMP specialist
Bill Gruenloh, normal air contains hundreds of millions of particles per cubic
foot. Air handlers and HEPA filters reduce the number of particles in the
manufacturing room to only 10,000. Areas under tissue culture hoods have just
100. In addition, the highly specialized GMP employees maintain meticulous
records of every article in the facility. A computer constantly monitors the
GMP, and the employees double-check readings with hand-held instruments. Thus
no micro-organisms are present in critical areas of the GMP.
If a contamination or other problem
occurs with a test drug, the GMP records help trace the cause, Gruenloh said.
UC Davis GMP specialist John Walker at work (photo by Gene Veritas)
The GMP also stores stem cells and other
items at carefully controlled, very low temperatures. The UC Davis GMP
developed the first GMP-grade cell-sorter in the world, Gruenloh added.
In addition, the GMP houses its own
quality control lab to check the safety of products and verify that they are
free of contaminants and bacteria.
Putting
the project in perspective
As Dr. Nolta has pointed out on several
occasions, more than 10,000 patients worldwide have already received MSCs
infused into the blood stream. In fact, the drug regulatory agencies of Canada
and New Zealand have already approved the use of MSCs to be prescribed as a
drug to treat certain diseases, although not yet HD. In addition, at least four
companies are currently testing MSCs or MSC-like cells in clinical trials for
other neurodegenerative conditions.
As always, we need to recall that only
10 percent of clinical trials ever lead to an actual drug. Mathematically
speaking, the odds are stacked against the Nolta-Wheelock project.
Even if the Phase I trial proves a
dramatic success, the UC Davis team will need to find ways to fund Phases II
and III, which will require larger numbers of participants and thus cost more
money. Backed by public bonds, CIRM will run out of money in about four years,
unless the agency can attract private investors. At least for now, the state of
California’s dire fiscal situation makes further public funding unlikely,
although one cannot predict the mood of the voters.
With an eye to the future, Dr. Nolta and
UC Davis have secured a patent for the MSC siRNA delivery technology in the
hopes that a pharmaceutical firm or other private investor might risk
supporting further research and testing in exchange for some of the potential
profits from a drug. She noted that companies visit the IRC regularly, although
none has yet expressed an interest in supporting HD work.
Despite these caveats, I am struck by
the apparent simplicity of the UC Davis approach: using human cells as a way to deliver remedies to the brain.
I am also impressed with the UC Davis
team’s boldness in moving as quickly as possible towards a clinical trial. In
fact, some scientists think they’re moving too quickly with their siRNA plans, although Dr. Nolta characterized their criticism as
a “misunderstanding” of her project, since it is the BDNF trial, not the siRNA,
that is moving toward the clinic first. The siRNA studies are only in early
rodent testing.
A successful MSC HD trial would extend
immense hope to patients suffering from other neurological diseases (such as Alzheimer’s
and Parkinson’s), as well as ischemia, heart disease, and other conditions, Dr.
Nolta said. Such hope would likely translate into greater private funding for
MSC research.
Hope,
realism, and future advocacy
California’s HD stem cell advocates –
along with fellow HD activists around the world – can feel confident that CIRM
is having an important impact on HD research.
We now await the MSC trial results – and
with great hope!
However, we should also proceed with
patience and realism.
Science takes time.
Furthermore, most scientists think that
treating HD successfully will require a cocktail
of remedies, not just one.
With grassroots support for, and intense
interest in, the UC Davis HD program, the HD community is betting heavily that
MSCs will provide a way to alleviate the conditions’ horrific symptoms.
Judging from the unprecedented excitement
about the CIRM grant that I have witnessed in the HD Facebook community in
comparison with news about other breakthroughs, I think people perceive stem
cells as providing the greatest hope. Indeed, for many Americans, stem cells
seem to hold an almost magical appeal, as they once did for the young Jan Nolta
at the start of her career. People seem to sense viscerally that they can
provide cures and replace lost cells and tissues. Could stem cells represent
our new Fountain of Youth?
Naturally, we all want, need, and
deserve to celebrate the CIRM award.
I myself have advocated for California stem cell research for more than a decade through HDSA-San Diego. Having lost
my mother to HD in 2006 at the age of 68 and tested positive for HD in 1999, I
anxiously await treatments. When people told me that potential stem cell
breakthroughs lay too far in the future to offer me hope, my resolve to fight
only strengthened.
Yet we should also keep in mind that
scientists are working just as hard on numerous other, highly important
approaches. They don’t stir the controversy and publicity that have surrounded
stem cells, and many are extremely difficult to understand, but they could very
well lead to effective treatments.
In effect, the Nolta-Wheelock project is
another “shot on goal” in the search for HD treatments. The CHDI Foundation,Inc., the major private backer of HD drug research, and its collaborators will attempt as many as eight such shots in the next few years. The more
shots, the better the chances of finding treatments and a
cocktail.
In the meantime, just as Dr. Nolta, the
UC Davis team, and scientists around the world work feverishly to liberate us
from HD, we in the HD community must continue to strategically advocate for our
cause, creatively help change the course of science, and participate in
the crucial research studies and clinical trials that provide the key to
defeating HD.
* * *
Additional
information
Once the UC Davis trial is approved the
FDA, details of how to participate will become available at www.clinicaltrials.gov.
For an HD family member’s account of the
historic CIRM meeting, read Katie Jackson’s report at The Huntington’s Post.
To learn more about Dr. Nolta’s
research, read an article by Dr. Marsha Miller by clicking here.
For the official CIRM evaluation of the
project, please click here.
To see a presentation by Dr. Nolta on
MSCs and HD, watch the video below.
Towards Stem-Cell Treatments for Huntington's Disease: Talk by Dr. Jan Nolta from
Gene Veritas on
Vimeo.
