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CLINICAL TRIALS BRING MIND’S SCIENCE
Adenosine A 2A Receptors and
Parkinson’s Disease—Coffee
Provides Clues
Intriguing data from
epidemiological studies
have shown that that
consumption of coffee
and other forms of caffeine is associated with a
lower risk of developing
Parkinson’s disease (PD).
Michael Schwarzschild,
MD, PhD has investigated
how caffeine’s effects on
specific brain cell receptors may help protect cells. Receptors are molecules on the surface of the
cell that can receive signals from other cells. Adenosine A2A receptors,
which are plentiful in the region of the brain that is affected in Parkinson’s
disease, are involved in controlling movement and are sensitive to caffeine.
Research suggests that drugs that block the receptors can partially
reverse motor deficits.
Dr. Schwarzschild plays a leading role in investigating how all this information
may inform the development of new PD treatments. In 2006, 200 neuroscientists and physicians from around the world, as well as pharmaceutical
and biotechnology industry experts, convened at Mass General to share
research. The conference—Targeting Adenosine A2A Receptors in
Parkinson’s Disease and other CNS Disorders—was co-chaired by Dr.
Schwarzschild and covered new basic science advances, clinical trials of
drugs that block the receptors, and strategies to accelerate the translation
of newfound knowledge into viable therapies for PD.
Dr. Schwarzschild is also interested in how A2A receptors may be manipulated to reduce dyskinesia—the excessive movements that can be a disabling
side effect of long term treatment with L-dopa, the mainstay therapy for
PD. His lab has shown that blocking adenosine receptors can prevent
dyskinesia-like activity in parkinsonian mice that have been treated with
L-dopa. His research group has also examined the potential interactions
between A2A receptors and estrogen, because epidemiological studies
have shown that caffeine is linked to a reduced risk of PD only in those
women who have not taken post-menopausal estrogen replacement
therapy. “We are fortunate to have collaborations that allow us to study
large populations over time to see what may contribute to developing
PD—this rich and varied information provides clues to pursue in the
laboratory and eventually will lead to medicines that work in patients,”
said Dr. Schwarzschild.
Industry Partnerships
Accelerate Treatment
One of the goals of the creation of MIND five years
ago was to enlist interest from pharmaceutical and
biotech companies to work on these difficult diseases, especially those like HD and ALS which are
“orphan diseases”—affecting relatively few patients.
Our goal became a reality this year when MIND
signed a groundbreaking agreement with Novartis, a
world leader in drug discovery. The agreement will
bring together teams from MIND, MIT and Novartis
to work collaboratively on Huntington’s disease
therapies. It is the first time a large pharmaceutical
company has made a substantial commitment to
tackle Huntington’s disease, bringing intellectual, scientific, and financial resources to the research, including
Novartis’s formidable drug compound library. All the
partners believe the collaboration will accelerate the
process of finding and testing new drugs.
"Our goal is to help patients now and in the future.
When the molecular basis of disease comes into focus,
as for HD, we ask how readily we can gain a therapeutic foothold. In this case, the discoveries of colleagues
in MIND and MIT provide a fantastic basis for potential
stated Mark Fishman, MD, President of the Novartis
Institutes for BioMedical Research.
MIND’s Day Laboratory for Neuromuscular Research
has joined forces with the newly created AviTx to
develop novel approaches to ALS treatment. This
company was created by Avi Kremer, a Harvard
Business School student who was diagnosed with ALS
in 2004. Having raised more than $2 million for ALS
research, he has turned his attention to biotech
approaches for delivery of therapeutics to the brain,
which is a considerable challenge in all brain diseases
since it is difficult to get compounds to cross the
blood-brain barrier. Dr. Jonathan Francis is working
with Dr. Robert Brown, Director of the Day Lab, and
AviTx to examine whether a non-toxic fragment of
tetanus can improve delivery of neuronal growth
factors to the particular nerve cells that are dying in
ALS. If this approach is successful in ALS, it could be
used in other diseases that also require drug delivery
to the brain.
The mission of MIND is to accelerate the translation of
basic research into the development of drugs to help
patients. To further this goal, MGH has created a
Neurology Clinical Trials Unit led by Merit Cudkowicz,
MD and Steven Greenberg, MD, PhD to assist in the
design and implementation of clinical trials as well as
the education and recruitment of patient subjects.
Concepts that have been proven at the molecular level in
the test tube undergo an arduous process to determine
if a research advance could be transformed into new drug
discovery. Once a molecule is identified that protects cells
in the test tube, it must undergo extensive modification
and re-testing to determine whether the intended effects
are actually attributable to the drug and reproducible
in various models—which could include cells, fruit
flies, and worms. Compounds that pass these hurdles
can then be tested in mice which display symptoms of the
various neurodegenerative diseases. Drugs that improve
functioning and prolong survival in several different trials
in mice are then brought forward to human clinical trials.
Human clinical trials go through three separate phases
to assess a drug’s effectiveness, compare it against existing
treatments and identify all side effects in increasingly
larger and more diverse patient populations. In order
to expedite clinical trials and assure unbiased results,
MGH neurologists are members of several nonprofit,
academic clinical research groups which can enroll large
populations and are dedicated to the dissemination of
both positive and negative results of clinical studies.
Currently, many clinical trials are underway or will enroll
soon at MGH, all of which had their beginnings in
laboratory benches at MIND or at other institutions
around the world, for example:
• Antibiotics are being tested for their neuroprotective
properties in ALS and HD;
• The nutritional supplements coenzyme Q10 and
creatine are being tested for their ability to improve
cellular energy and therefore brain cell function in
HD, PD and ALS;
TO THE
P AT I E N T
“I participate in
clinical trials because I
want to be part of moving
treatment forward, plus
I learn so much every
time I go in—the flow of
information is great.
When I saw the research
labs at MIND I was overwhelmed and amazed at
everything going on and
proud to be part of it.”
Todd Bliss, patient at MGH
• An antibody treatment that triggers a person’s immune
system to clear toxic protein from the brain is being
tested for Alzheimer’s disease;
• Two drugs that stop protein aggregation are being
tested in ALS;
• An experimental drug that acts as a dopamine agonist
is being tested for Parkinson’s disease.
In addition to these and other drug studies, MGH
researchers are also invested in finding biomarkers for
neurodegenerative diseases. These important studies
look for molecules in the blood or spinal fluid and
changes in brain imaging to find ways to diagnose
diseases earlier and track the progression accurately
with objective measures.
For more information on clinical trials
please talk to your Mass General neurologist
or email the Neurology Clinical Trials Unit at
[email protected].
MassGeneral Institute for Neurodegenerative Disease
114 16th Street
Charlestown, Massachusetts 02129
617.726.1278
email: [email protected]
www.mghmind.org
MASSACHUSETTS ALZHEIMER'S
DISEASE RESEARCH CENTER
JAN 2007
RESEARCH
R E V I E W
Collaborating for Cures
Reaching Drug Discovery Milestones in Alzheimer’s,
ALS, Huntington’s, and Parkinson’s Disease
Dr. Anne Young and patient Todd Bliss in the MIND
drug discovery laboratory.
Three years of hard work perfecting drug discovery
techniques at the MassGeneral Institute for
Neurodegenerative Disease has begun to pay off
with several promising projects. The protein
clearance drug “C2-8” that was discovered last year
as a potential treatment for Huntington’s disease
has shown positive results in the first series of
mouse trials and is currently being tested in a
different mouse model of the disease to see if it
can protect brain cells from degenerating.
Protein misfolding is a central concept in all the
neurodegenerative diseases. In Parkinson’s and
Lewy Body disease, the protein alpha-synuclein misfolds and forms clumps. Tiago Outeiro, PhD,
working in Dr. Brad Hyman’s laboratory, has collaborated with Dr. Alex Kazantsev to screen for
drugs that affect the toxic folding and clumping of this protein in brain cells. They discovered a
promising compound that seems to work in both Huntington’s disease cells and even more
powerfully in Parkinson’s disease cells. Work is ongoing to refine this compound and seek even
stronger agents with the same effects.
In Alzheimer’s disease, cholesterol has been implicated as contributing to the accumulation of
A-beta, the toxic protein piece that forms plaques in the brain. A two part study led by Dora
Kovacs, PhD is currently underway at MIND to see if compounds that prevent or decrease the
production of A-beta by altering cholesterol production in the brain could be effective. These
drugs, called ACAT inhibitors, were originally developed for heart disease. An initial study showed
that one type of inhibitor reduced plaques in the AD mouse brain. Currently underway is a
complementary study with another ACAT inhibitor that has previously reached phase III trials
(found to be safe) in humans. If it is shown to be effective in mice, it could go forward to human
trials quickly. This project is generously supported by the Cure Alzheimer’s Fund.
Drug discovery efforts in Dr. Robert Brown’s laboratory received an important boost recently
with the award of a federal grant to enhance the laboratory’s impressive array of drug screening
projects for ALS and other neuromuscular disorders. This grant builds on Dr. Brown’s
expertise in this area and supports collaboration with former MIND investigators Dr. Piera
Pasinelli and Dr. Davide Trotti, now both at Thomas Jefferson University. Dr. Brown will utilize
their cell-based assays that mimic ALS in the Petri dish to screen thousands of compounds that
have the potential to be developed into drugs for ALS. Compounds which show promise can then
be enhanced and modified for use in mouse trials.
An enzyme known to be critical for the repair of damaged cells and the maintenance of cellular
energy has been identified as a target for new strategies to treat Huntington's, Parkinson’s,
and other disorders characterized by low cellular energy. This enzyme is known as PARP1 and
Dr. Alex Kazantsev has discovered a small molecule compound that inhibits its activity and thereby can protect both HD-affected cells and PD cells from death in laboratory test tube.This small
molecule has the potential to be developed into a drug not only for HD and PD but could be
beneficial for cancer and over twenty other human disorders. Further work is currently underway
to refine this molecule, strengthen it, and prepare for animal testing.
MESSAGE FROM DR.YOUNG
MIND is five years old and we
have so much to celebrate.
Amazingly, both our research
budget and our staff has doubled.
Our resulting tight quarters,
while sometimes inconvenient,
also encourage scientists to bump
into each other, share ideas, and
initiate fruitful collaborations. This
review highlights some work, but
there is not enough space to
describe all the progress or the
enthusiasm that is so tangible
when I walk around the institute.
Our scientists are not locked in
isolated laboratories—every
advance in the lab must answer
the question—how could this
new idea help patients today?
As a result, MIND has turned
many breakthroughs into drug
discovery projects, finding seven
compounds that have the
potential to be developed into
drugs, surpassing the results of
some large biotech companies.
How do we do it? Interaction,
innovation, intuition, and—most
importantly—investments from
committed patients and friends
who believe that we can and
must cure these diseases.Thank
you for that support, and please
continue to invest in our work,
because we need it now more
than ever.
Anne Young, MD, PhD
Chief of Neurology,
Scientific Director, MIND
Genetic Investigations
Provide Hope for ALS
Phyllis Rappaport, Co-Founder Cure Alzheimer's Fund and
member of Friends of MIND.
Curing Alzheimer’s Gene by
Gene
MIND researchers, led by Rudy Tanzi, PhD, are
mining the human genome to discover which
genes increase susceptibility for the development
of Alzheimer’s disease (AD). Using a large and
powerful set of more than 400 families afflicted
with AD, collected at MGH and elsewhere, Dr.
Tanzi has launched the Alzheimer’s Genome
Project. Cutting-edge statistical programs that
have become available in the last two years now
allow researchers to query thousands of genes
simultaneously on high tech “gene chips”. They
can then analyze this information with sophisticated computers, resulting in astoundingly rich
information. The massive project will include
genotyping, analyses, follow-up, and confirmatory
studies to hopefully identify more than 90% of
all remaining Alzheimer’s genes. This project is
generously funded by a new foundation, the Cure
Alzheimer’s Fund, which takes a venture approach
to philanthropy, seeking high risk projects which
have the potential for high return.
“My generation has changed the world in many
positive ways, but as we age,Alzheimer’s and the
care we demand is going to bankrupt the health
care system. I don’t want that to be our legacy,”
said Phyllis Rappaport, Co-Founder, Cure
Alzheimer’s Fund. “I believe that the approach
mapped out by Rudy Tanzi and others at MIND is
a well managed path of research that will improve
our future and our children’s future.”
Continuing his laboratory’s groundbreaking research on ALS by exploring the
human genome, Dr. Robert Brown and international collaborators have made
two important genetic discoveries and have launched a comprehensive
genome screen to identify other susceptibility genes for ALS.
Dr. Brown and colleagues found that mutations in the ANG gene on
chromosome 14 may be the cause of ALS in patients from Scotland and
Ireland and also may explain higher rates of ALS in those countries. This
mutation provides an important clue to the cause of ALS since the protein
which it encodes, angiogenin, is involved in blood vessel growth and can cause
oxidative stress. The investigators studied 1,600 people with ALS and 1,200
without it. Of those with ALS, 15 had mutations in this gene and all of these
were of Irish or Scottish descent, most with family histories of the disease.
There was only one person who had the mutation and did not develop ALS,
suggesting that more than just this gene determines susceptibility. Also, since
the vast majority of ALS patients did not carry this mutation, it may be one of
numerous different causes of ALS.
Dr. Robert Brown
Dr. Brown was also part of a team
that studied a Scandinavian family
that had both ALS in the family as well
as frontotemporal dementia, another
neurodegenerative disease.This group
found that a gene on chromosome 9
was defective in all the cases that
resulted in either neurodegenerative
disease—but that no patients had
both ALS and dementia, suggesting
that another factor was at play.
The Day Laboratory also embarked on another tack to understand noninherited ALS. In an effort that parallels the Alzheimer’s Genome Project (see
article on Dr. Tanzi’s work), Dr. Brown is in the midst of a screen of the
human genome involving 1,000 ALS patients and 1,000 people without ALS
to see which genetic differences may increase the risk for developing the
disease. Insights into such risk factors in ALS will both help elucidate the
cause of the illness and assist in the design of new therapies. This work is
generously funded by the ALS Therapy Alliance, Project ALS (via the Harvard
Center for Neurodegeneration and Repair), the Angel Fund, and the British
Motor Neuron Disease Association. The ALS Therapy Alliance is funded
through a nationwide customer donation campaign for ALS research
conducted by CVS/pharmacy.
Protein Interactions Implicated in
Alzheimer’s Disease
MIND researcher Suzanne Guenette, PhD continues her important study of
proteins that interact with APP—the amyloid precursor protein— a central
target in Alzheimer's disease. APP is cleaved into toxic pieces that result in
the accumulation of A-beta and ultimately the development of amyloid plaques
in the Alzheimer's brain. Dr. Guenette's work is focused on examining the
proteins that interact with APP to see if we can better understand the function
Dr Guenette and team in lab.
of APP and find possible interventions to reduce its toxicity. Guenette has
focused on the FE65 proteins which bind to APP—showing that without FE65 proteins, mice show severe abnormalities in the brain’s
cortex, similar to mice lacking all APP proteins, thus suggesting that these proteins must work together for neural development.
Recent studies have also shown that the FE65-binding region of APP has been implicated in the development of AD in mouse models.
All this work suggests that targeting the FE65’s, instead of APP directly, may be an alternative way to affect disease progression in
Alzheimer’s.
Not an Optical Illusion: Imaging
Breakthroughs in Alzheimer’s
Just as CT scans, MRI’s and PET scans have transformed medical care, new forms
of microscopy and imaging have allowed MIND scientists to see inside the brain
to better understand Alzheimer’s disease (AD) pathology. Multi-photon microscopes are used to see changes in animal models, and to compare diseased
brains with normal aging. Bradley Hyman, MD, PhD, and Brian Bacskai, PhD, lead
a group of scientists in this endeavor, and their work has resulted in stunning
visual records of the development of AD in mouse brains over time, as well as
the clearance of AD plaques by the application of therapeutic agents that act like
vaccines against amyloid.
A multiphoton microscope image from a live mouse
shows stained blue amyloid plaques, green dendrites, and
red blood vessels. Dendrites lose spines near plaques.
One project completed in the last year involves examining neurons’ dendritic
spines—small spider-like protrusions from the cell—that are essential to the responsiveness and plasticity underlying learning and
memory. In post mortem human AD brains, these structures are reduced. Dr. Tara Spires, working in Dr. Hyman’s unit, has been
able to study exactly how and where these spines form, and their demise over time, in the living brains of mice who are developing
a mouse form of AD. She showed how AD plaques seem to cause the cells to lose spines and presumably, the connections between
cells that are critical for making memories. Her work provides one more clue that drugs which prevent plaque formation may keep
the dendrites, and thereby the connections between brain cells, alive and functioning.
Solving the Puzzle of Gene
Transcription in HD
MIND investigators are zeroing in on transcription
—the process by which neurons read particular
portions of the genome and turn genes on or
off—as a central mechanism that malfunctions in
Huntington’s disease (HD), with ruinous consequences
for brain function. Inquiries are also expanding to
include the other neurodegenerative diseases and
normal aging.
In Dr. Jang-Ho Cha’s lab, this approach to studying
transcription is now taking into consideration
another hallmark of disease pathology—large
clumps of misfolded protein in brain cells.Whether
Dr. Ghazaleh Sadri-Vakili (r) is an Instructor in
these clumps, called nuclear inclusions, cause the
the laboratory of Dr. Jang-Ho Cha (l) who
disease or are a by-product of degeneration, has
investigates gene transcription.
been hotly debated. Since problems in transcription
have been well documented by Dr. Cha’s laboratory
as well as other researchers, his team completed a series of experiments to elucidate the
relationship between these two observed pathologies. Dr. Ghazaleh Sadri-Vakili, working in
Dr. Cha's group, found that brain cells with nuclear inclusions did not show different patterns
of transcription than cells without these obvious clumps. These findings imply that nuclear
inclusions neither contribute to transcription dysregulation nor protect the brain cell against
it. More important, it means that clearing or preventing nuclear inclusions is not likely to
improve transcription activities in the affected brain cells.
Dimitri Krainc, MD, PhD, has found an important clue. His recent research links problems with
transcription to the functioning of mitochondria, the power plant of the cell. In Huntington’s
and several other neurodegenerative diseases, there is marked alteration
in the mitochondria’s ability to produce energy from glucose and oxygen,
resulting in the dramatic weight loss and increased demand for calories
seen in HD and other neurodegenerative diseases. Dr. Krainc has shown
that the abnormal form of the huntingtin protein, the product of the
HD gene mutation, interferes with the production of a protein critical to
cellular energy metabolism—protein PGC-1a. This discovery is the first
to bring together two processes believed to be involved in the pathology
of HD—the conversion of genetic information into proteins and the
production of energy within cells.
Dr. Dimitri Krainc
“Our study indicates that these two disease mechanisms are linked.
Disruption of gene transcription by mutant huntingtin leads to abnormal energy metabolism,
which affects cellular processes and results in neurodegeneration,” says Dr. Krainc. His group
is now beginning to search for new compounds that could correct PGC-1a dysregulation and
potentially reverse the disruption of energy metabolism in HD.
Genetic Investigations
Provide Hope for ALS
Phyllis Rappaport, Co-Founder Cure Alzheimer's Fund and
member of Friends of MIND.
Curing Alzheimer’s Gene by
Gene
MIND researchers, led by Rudy Tanzi, PhD, are
mining the human genome to discover which
genes increase susceptibility for the development
of Alzheimer’s disease (AD). Using a large and
powerful set of more than 400 families afflicted
with AD, collected at MGH and elsewhere, Dr.
Tanzi has launched the Alzheimer’s Genome
Project. Cutting-edge statistical programs that
have become available in the last two years now
allow researchers to query thousands of genes
simultaneously on high tech “gene chips”. They
can then analyze this information with sophisticated computers, resulting in astoundingly rich
information. The massive project will include
genotyping, analyses, follow-up, and confirmatory
studies to hopefully identify more than 90% of
all remaining Alzheimer’s genes. This project is
generously funded by a new foundation, the Cure
Alzheimer’s Fund, which takes a venture approach
to philanthropy, seeking high risk projects which
have the potential for high return.
“My generation has changed the world in many
positive ways, but as we age,Alzheimer’s and the
care we demand is going to bankrupt the health
care system. I don’t want that to be our legacy,”
said Phyllis Rappaport, Co-Founder, Cure
Alzheimer’s Fund. “I believe that the approach
mapped out by Rudy Tanzi and others at MIND is
a well managed path of research that will improve
our future and our children’s future.”
Continuing his laboratory’s groundbreaking research on ALS by exploring the
human genome, Dr. Robert Brown and international collaborators have made
two important genetic discoveries and have launched a comprehensive
genome screen to identify other susceptibility genes for ALS.
Dr. Brown and colleagues found that mutations in the ANG gene on
chromosome 14 may be the cause of ALS in patients from Scotland and
Ireland and also may explain higher rates of ALS in those countries. This
mutation provides an important clue to the cause of ALS since the protein
which it encodes, angiogenin, is involved in blood vessel growth and can cause
oxidative stress. The investigators studied 1,600 people with ALS and 1,200
without it. Of those with ALS, 15 had mutations in this gene and all of these
were of Irish or Scottish descent, most with family histories of the disease.
There was only one person who had the mutation and did not develop ALS,
suggesting that more than just this gene determines susceptibility. Also, since
the vast majority of ALS patients did not carry this mutation, it may be one of
numerous different causes of ALS.
Dr. Robert Brown
Dr. Brown was also part of a team
that studied a Scandinavian family
that had both ALS in the family as well
as frontotemporal dementia, another
neurodegenerative disease.This group
found that a gene on chromosome 9
was defective in all the cases that
resulted in either neurodegenerative
disease—but that no patients had
both ALS and dementia, suggesting
that another factor was at play.
The Day Laboratory also embarked on another tack to understand noninherited ALS. In an effort that parallels the Alzheimer’s Genome Project (see
article on Dr. Tanzi’s work), Dr. Brown is in the midst of a screen of the
human genome involving 1,000 ALS patients and 1,000 people without ALS
to see which genetic differences may increase the risk for developing the
disease. Insights into such risk factors in ALS will both help elucidate the
cause of the illness and assist in the design of new therapies. This work is
generously funded by the ALS Therapy Alliance, Project ALS (via the Harvard
Center for Neurodegeneration and Repair), the Angel Fund, and the British
Motor Neuron Disease Association. The ALS Therapy Alliance is funded
through a nationwide customer donation campaign for ALS research
conducted by CVS/pharmacy.
Protein Interactions Implicated in
Alzheimer’s Disease
MIND researcher Suzanne Guenette, PhD continues her important study of
proteins that interact with APP—the amyloid precursor protein— a central
target in Alzheimer's disease. APP is cleaved into toxic pieces that result in
the accumulation of A-beta and ultimately the development of amyloid plaques
in the Alzheimer's brain. Dr. Guenette's work is focused on examining the
proteins that interact with APP to see if we can better understand the function
Dr Guenette and team in lab.
of APP and find possible interventions to reduce its toxicity. Guenette has
focused on the FE65 proteins which bind to APP—showing that without FE65 proteins, mice show severe abnormalities in the brain’s
cortex, similar to mice lacking all APP proteins, thus suggesting that these proteins must work together for neural development.
Recent studies have also shown that the FE65-binding region of APP has been implicated in the development of AD in mouse models.
All this work suggests that targeting the FE65’s, instead of APP directly, may be an alternative way to affect disease progression in
Alzheimer’s.
Not an Optical Illusion: Imaging
Breakthroughs in Alzheimer’s
Just as CT scans, MRI’s and PET scans have transformed medical care, new forms
of microscopy and imaging have allowed MIND scientists to see inside the brain
to better understand Alzheimer’s disease (AD) pathology. Multi-photon microscopes are used to see changes in animal models, and to compare diseased
brains with normal aging. Bradley Hyman, MD, PhD, and Brian Bacskai, PhD, lead
a group of scientists in this endeavor, and their work has resulted in stunning
visual records of the development of AD in mouse brains over time, as well as
the clearance of AD plaques by the application of therapeutic agents that act like
vaccines against amyloid.
A multiphoton microscope image from a live mouse
shows stained blue amyloid plaques, green dendrites, and
red blood vessels. Dendrites lose spines near plaques.
One project completed in the last year involves examining neurons’ dendritic
spines—small spider-like protrusions from the cell—that are essential to the responsiveness and plasticity underlying learning and
memory. In post mortem human AD brains, these structures are reduced. Dr. Tara Spires, working in Dr. Hyman’s unit, has been
able to study exactly how and where these spines form, and their demise over time, in the living brains of mice who are developing
a mouse form of AD. She showed how AD plaques seem to cause the cells to lose spines and presumably, the connections between
cells that are critical for making memories. Her work provides one more clue that drugs which prevent plaque formation may keep
the dendrites, and thereby the connections between brain cells, alive and functioning.
Solving the Puzzle of Gene
Transcription in HD
MIND investigators are zeroing in on transcription
—the process by which neurons read particular
portions of the genome and turn genes on or
off—as a central mechanism that malfunctions in
Huntington’s disease (HD), with ruinous consequences
for brain function. Inquiries are also expanding to
include the other neurodegenerative diseases and
normal aging.
In Dr. Jang-Ho Cha’s lab, this approach to studying
transcription is now taking into consideration
another hallmark of disease pathology—large
clumps of misfolded protein in brain cells.Whether
Dr. Ghazaleh Sadri-Vakili (r) is an Instructor in
these clumps, called nuclear inclusions, cause the
the laboratory of Dr. Jang-Ho Cha (l) who
disease or are a by-product of degeneration, has
investigates gene transcription.
been hotly debated. Since problems in transcription
have been well documented by Dr. Cha’s laboratory
as well as other researchers, his team completed a series of experiments to elucidate the
relationship between these two observed pathologies. Dr. Ghazaleh Sadri-Vakili, working in
Dr. Cha's group, found that brain cells with nuclear inclusions did not show different patterns
of transcription than cells without these obvious clumps. These findings imply that nuclear
inclusions neither contribute to transcription dysregulation nor protect the brain cell against
it. More important, it means that clearing or preventing nuclear inclusions is not likely to
improve transcription activities in the affected brain cells.
Dimitri Krainc, MD, PhD, has found an important clue. His recent research links problems with
transcription to the functioning of mitochondria, the power plant of the cell. In Huntington’s
and several other neurodegenerative diseases, there is marked alteration
in the mitochondria’s ability to produce energy from glucose and oxygen,
resulting in the dramatic weight loss and increased demand for calories
seen in HD and other neurodegenerative diseases. Dr. Krainc has shown
that the abnormal form of the huntingtin protein, the product of the
HD gene mutation, interferes with the production of a protein critical to
cellular energy metabolism—protein PGC-1a. This discovery is the first
to bring together two processes believed to be involved in the pathology
of HD—the conversion of genetic information into proteins and the
production of energy within cells.
Dr. Dimitri Krainc
“Our study indicates that these two disease mechanisms are linked.
Disruption of gene transcription by mutant huntingtin leads to abnormal energy metabolism,
which affects cellular processes and results in neurodegeneration,” says Dr. Krainc. His group
is now beginning to search for new compounds that could correct PGC-1a dysregulation and
potentially reverse the disruption of energy metabolism in HD.
Genetic Investigations
Provide Hope for ALS
Phyllis Rappaport, Co-Founder Cure Alzheimer's Fund and
member of Friends of MIND.
Curing Alzheimer’s Gene by
Gene
MIND researchers, led by Rudy Tanzi, PhD, are
mining the human genome to discover which
genes increase susceptibility for the development
of Alzheimer’s disease (AD). Using a large and
powerful set of more than 400 families afflicted
with AD, collected at MGH and elsewhere, Dr.
Tanzi has launched the Alzheimer’s Genome
Project. Cutting-edge statistical programs that
have become available in the last two years now
allow researchers to query thousands of genes
simultaneously on high tech “gene chips”. They
can then analyze this information with sophisticated computers, resulting in astoundingly rich
information. The massive project will include
genotyping, analyses, follow-up, and confirmatory
studies to hopefully identify more than 90% of
all remaining Alzheimer’s genes. This project is
generously funded by a new foundation, the Cure
Alzheimer’s Fund, which takes a venture approach
to philanthropy, seeking high risk projects which
have the potential for high return.
“My generation has changed the world in many
positive ways, but as we age,Alzheimer’s and the
care we demand is going to bankrupt the health
care system. I don’t want that to be our legacy,”
said Phyllis Rappaport, Co-Founder, Cure
Alzheimer’s Fund. “I believe that the approach
mapped out by Rudy Tanzi and others at MIND is
a well managed path of research that will improve
our future and our children’s future.”
Continuing his laboratory’s groundbreaking research on ALS by exploring the
human genome, Dr. Robert Brown and international collaborators have made
two important genetic discoveries and have launched a comprehensive
genome screen to identify other susceptibility genes for ALS.
Dr. Brown and colleagues found that mutations in the ANG gene on
chromosome 14 may be the cause of ALS in patients from Scotland and
Ireland and also may explain higher rates of ALS in those countries. This
mutation provides an important clue to the cause of ALS since the protein
which it encodes, angiogenin, is involved in blood vessel growth and can cause
oxidative stress. The investigators studied 1,600 people with ALS and 1,200
without it. Of those with ALS, 15 had mutations in this gene and all of these
were of Irish or Scottish descent, most with family histories of the disease.
There was only one person who had the mutation and did not develop ALS,
suggesting that more than just this gene determines susceptibility. Also, since
the vast majority of ALS patients did not carry this mutation, it may be one of
numerous different causes of ALS.
Dr. Robert Brown
Dr. Brown was also part of a team
that studied a Scandinavian family
that had both ALS in the family as well
as frontotemporal dementia, another
neurodegenerative disease.This group
found that a gene on chromosome 9
was defective in all the cases that
resulted in either neurodegenerative
disease—but that no patients had
both ALS and dementia, suggesting
that another factor was at play.
The Day Laboratory also embarked on another tack to understand noninherited ALS. In an effort that parallels the Alzheimer’s Genome Project (see
article on Dr. Tanzi’s work), Dr. Brown is in the midst of a screen of the
human genome involving 1,000 ALS patients and 1,000 people without ALS
to see which genetic differences may increase the risk for developing the
disease. Insights into such risk factors in ALS will both help elucidate the
cause of the illness and assist in the design of new therapies. This work is
generously funded by the ALS Therapy Alliance, Project ALS (via the Harvard
Center for Neurodegeneration and Repair), the Angel Fund, and the British
Motor Neuron Disease Association. The ALS Therapy Alliance is funded
through a nationwide customer donation campaign for ALS research
conducted by CVS/pharmacy.
Protein Interactions Implicated in
Alzheimer’s Disease
MIND researcher Suzanne Guenette, PhD continues her important study of
proteins that interact with APP—the amyloid precursor protein— a central
target in Alzheimer's disease. APP is cleaved into toxic pieces that result in
the accumulation of A-beta and ultimately the development of amyloid plaques
in the Alzheimer's brain. Dr. Guenette's work is focused on examining the
proteins that interact with APP to see if we can better understand the function
Dr Guenette and team in lab.
of APP and find possible interventions to reduce its toxicity. Guenette has
focused on the FE65 proteins which bind to APP—showing that without FE65 proteins, mice show severe abnormalities in the brain’s
cortex, similar to mice lacking all APP proteins, thus suggesting that these proteins must work together for neural development.
Recent studies have also shown that the FE65-binding region of APP has been implicated in the development of AD in mouse models.
All this work suggests that targeting the FE65’s, instead of APP directly, may be an alternative way to affect disease progression in
Alzheimer’s.
Not an Optical Illusion: Imaging
Breakthroughs in Alzheimer’s
Just as CT scans, MRI’s and PET scans have transformed medical care, new forms
of microscopy and imaging have allowed MIND scientists to see inside the brain
to better understand Alzheimer’s disease (AD) pathology. Multi-photon microscopes are used to see changes in animal models, and to compare diseased
brains with normal aging. Bradley Hyman, MD, PhD, and Brian Bacskai, PhD, lead
a group of scientists in this endeavor, and their work has resulted in stunning
visual records of the development of AD in mouse brains over time, as well as
the clearance of AD plaques by the application of therapeutic agents that act like
vaccines against amyloid.
A multiphoton microscope image from a live mouse
shows stained blue amyloid plaques, green dendrites, and
red blood vessels. Dendrites lose spines near plaques.
One project completed in the last year involves examining neurons’ dendritic
spines—small spider-like protrusions from the cell—that are essential to the responsiveness and plasticity underlying learning and
memory. In post mortem human AD brains, these structures are reduced. Dr. Tara Spires, working in Dr. Hyman’s unit, has been
able to study exactly how and where these spines form, and their demise over time, in the living brains of mice who are developing
a mouse form of AD. She showed how AD plaques seem to cause the cells to lose spines and presumably, the connections between
cells that are critical for making memories. Her work provides one more clue that drugs which prevent plaque formation may keep
the dendrites, and thereby the connections between brain cells, alive and functioning.
Solving the Puzzle of Gene
Transcription in HD
MIND investigators are zeroing in on transcription
—the process by which neurons read particular
portions of the genome and turn genes on or
off—as a central mechanism that malfunctions in
Huntington’s disease (HD), with ruinous consequences
for brain function. Inquiries are also expanding to
include the other neurodegenerative diseases and
normal aging.
In Dr. Jang-Ho Cha’s lab, this approach to studying
transcription is now taking into consideration
another hallmark of disease pathology—large
clumps of misfolded protein in brain cells.Whether
Dr. Ghazaleh Sadri-Vakili (r) is an Instructor in
these clumps, called nuclear inclusions, cause the
the laboratory of Dr. Jang-Ho Cha (l) who
disease or are a by-product of degeneration, has
investigates gene transcription.
been hotly debated. Since problems in transcription
have been well documented by Dr. Cha’s laboratory
as well as other researchers, his team completed a series of experiments to elucidate the
relationship between these two observed pathologies. Dr. Ghazaleh Sadri-Vakili, working in
Dr. Cha's group, found that brain cells with nuclear inclusions did not show different patterns
of transcription than cells without these obvious clumps. These findings imply that nuclear
inclusions neither contribute to transcription dysregulation nor protect the brain cell against
it. More important, it means that clearing or preventing nuclear inclusions is not likely to
improve transcription activities in the affected brain cells.
Dimitri Krainc, MD, PhD, has found an important clue. His recent research links problems with
transcription to the functioning of mitochondria, the power plant of the cell. In Huntington’s
and several other neurodegenerative diseases, there is marked alteration
in the mitochondria’s ability to produce energy from glucose and oxygen,
resulting in the dramatic weight loss and increased demand for calories
seen in HD and other neurodegenerative diseases. Dr. Krainc has shown
that the abnormal form of the huntingtin protein, the product of the
HD gene mutation, interferes with the production of a protein critical to
cellular energy metabolism—protein PGC-1a. This discovery is the first
to bring together two processes believed to be involved in the pathology
of HD—the conversion of genetic information into proteins and the
production of energy within cells.
Dr. Dimitri Krainc
“Our study indicates that these two disease mechanisms are linked.
Disruption of gene transcription by mutant huntingtin leads to abnormal energy metabolism,
which affects cellular processes and results in neurodegeneration,” says Dr. Krainc. His group
is now beginning to search for new compounds that could correct PGC-1a dysregulation and
potentially reverse the disruption of energy metabolism in HD.
CLINICAL TRIALS BRING MIND’S SCIENCE
Adenosine A 2A Receptors and
Parkinson’s Disease—Coffee
Provides Clues
Intriguing data from
epidemiological studies
have shown that that
consumption of coffee
and other forms of caffeine is associated with a
lower risk of developing
Parkinson’s disease (PD).
Michael Schwarzschild,
MD, PhD has investigated
how caffeine’s effects on
specific brain cell receptors may help protect cells. Receptors are molecules on the surface of the
cell that can receive signals from other cells. Adenosine A2A receptors,
which are plentiful in the region of the brain that is affected in Parkinson’s
disease, are involved in controlling movement and are sensitive to caffeine.
Research suggests that drugs that block the receptors can partially
reverse motor deficits.
Dr. Schwarzschild plays a leading role in investigating how all this information
may inform the development of new PD treatments. In 2006, 200 neuroscientists and physicians from around the world, as well as pharmaceutical
and biotechnology industry experts, convened at Mass General to share
research. The conference—Targeting Adenosine A2A Receptors in
Parkinson’s Disease and other CNS Disorders—was co-chaired by Dr.
Schwarzschild and covered new basic science advances, clinical trials of
drugs that block the receptors, and strategies to accelerate the translation
of newfound knowledge into viable therapies for PD.
Dr. Schwarzschild is also interested in how A2A receptors may be manipulated to reduce dyskinesia—the excessive movements that can be a disabling
side effect of long term treatment with L-dopa, the mainstay therapy for
PD. His lab has shown that blocking adenosine receptors can prevent
dyskinesia-like activity in parkinsonian mice that have been treated with
L-dopa. His research group has also examined the potential interactions
between A2A receptors and estrogen, because epidemiological studies
have shown that caffeine is linked to a reduced risk of PD only in those
women who have not taken post-menopausal estrogen replacement
therapy. “We are fortunate to have collaborations that allow us to study
large populations over time to see what may contribute to developing
PD—this rich and varied information provides clues to pursue in the
laboratory and eventually will lead to medicines that work in patients,”
said Dr. Schwarzschild.
Industry Partnerships
Accelerate Treatment
One of the goals of the creation of MIND five years
ago was to enlist interest from pharmaceutical and
biotech companies to work on these difficult diseases, especially those like HD and ALS which are
“orphan diseases”—affecting relatively few patients.
Our goal became a reality this year when MIND
signed a groundbreaking agreement with Novartis, a
world leader in drug discovery. The agreement will
bring together teams from MIND, MIT and Novartis
to work collaboratively on Huntington’s disease
therapies. It is the first time a large pharmaceutical
company has made a substantial commitment to
tackle Huntington’s disease, bringing intellectual, scientific, and financial resources to the research, including
Novartis’s formidable drug compound library. All the
partners believe the collaboration will accelerate the
process of finding and testing new drugs.
"Our goal is to help patients now and in the future.
When the molecular basis of disease comes into focus,
as for HD, we ask how readily we can gain a therapeutic foothold. In this case, the discoveries of colleagues
in MIND and MIT provide a fantastic basis for potential
stated Mark Fishman, MD, President of the Novartis
Institutes for BioMedical Research.
MIND’s Day Laboratory for Neuromuscular Research
has joined forces with the newly created AviTx to
develop novel approaches to ALS treatment. This
company was created by Avi Kremer, a Harvard
Business School student who was diagnosed with ALS
in 2004. Having raised more than $2 million for ALS
research, he has turned his attention to biotech
approaches for delivery of therapeutics to the brain,
which is a considerable challenge in all brain diseases
since it is difficult to get compounds to cross the
blood-brain barrier. Dr. Jonathan Francis is working
with Dr. Robert Brown, Director of the Day Lab, and
AviTx to examine whether a non-toxic fragment of
tetanus can improve delivery of neuronal growth
factors to the particular nerve cells that are dying in
ALS. If this approach is successful in ALS, it could be
used in other diseases that also require drug delivery
to the brain.
The mission of MIND is to accelerate the translation of
basic research into the development of drugs to help
patients. To further this goal, MGH has created a
Neurology Clinical Trials Unit led by Merit Cudkowicz,
MD and Steven Greenberg, MD, PhD to assist in the
design and implementation of clinical trials as well as
the education and recruitment of patient subjects.
Concepts that have been proven at the molecular level in
the test tube undergo an arduous process to determine
if a research advance could be transformed into new drug
discovery. Once a molecule is identified that protects cells
in the test tube, it must undergo extensive modification
and re-testing to determine whether the intended effects
are actually attributable to the drug and reproducible
in various models—which could include cells, fruit
flies, and worms. Compounds that pass these hurdles
can then be tested in mice which display symptoms of the
various neurodegenerative diseases. Drugs that improve
functioning and prolong survival in several different trials
in mice are then brought forward to human clinical trials.
Human clinical trials go through three separate phases
to assess a drug’s effectiveness, compare it against existing
treatments and identify all side effects in increasingly
larger and more diverse patient populations. In order
to expedite clinical trials and assure unbiased results,
MGH neurologists are members of several nonprofit,
academic clinical research groups which can enroll large
populations and are dedicated to the dissemination of
both positive and negative results of clinical studies.
Currently, many clinical trials are underway or will enroll
soon at MGH, all of which had their beginnings in
laboratory benches at MIND or at other institutions
around the world, for example:
• Antibiotics are being tested for their neuroprotective
properties in ALS and HD;
• The nutritional supplements coenzyme Q10 and
creatine are being tested for their ability to improve
cellular energy and therefore brain cell function in
HD, PD and ALS;
TO THE
P AT I E N T
“I participate in
clinical trials because I
want to be part of moving
treatment forward, plus
I learn so much every
time I go in—the flow of
information is great.
When I saw the research
labs at MIND I was overwhelmed and amazed at
everything going on and
proud to be part of it.”
Todd Bliss, patient at MGH
• An antibody treatment that triggers a person’s immune
system to clear toxic protein from the brain is being
tested for Alzheimer’s disease;
• Two drugs that stop protein aggregation are being
tested in ALS;
• An experimental drug that acts as a dopamine agonist
is being tested for Parkinson’s disease.
In addition to these and other drug studies, MGH
researchers are also invested in finding biomarkers for
neurodegenerative diseases. These important studies
look for molecules in the blood or spinal fluid and
changes in brain imaging to find ways to diagnose
diseases earlier and track the progression accurately
with objective measures.
For more information on clinical trials
please talk to your Mass General neurologist
or email the Neurology Clinical Trials Unit at
[email protected].
MassGeneral Institute for Neurodegenerative Disease
114 16th Street
Charlestown, Massachusetts 02129
617.726.1278
email: [email protected]
www.mghmind.org
MASSACHUSETTS ALZHEIMER'S
DISEASE RESEARCH CENTER
JAN 2007
RESEARCH
R E V I E W
Collaborating for Cures
Reaching Drug Discovery Milestones in Alzheimer’s,
ALS, Huntington’s, and Parkinson’s Disease
Dr. Anne Young and patient Todd Bliss in the MIND
drug discovery laboratory.
Three years of hard work perfecting drug discovery
techniques at the MassGeneral Institute for
Neurodegenerative Disease has begun to pay off
with several promising projects. The protein
clearance drug “C2-8” that was discovered last year
as a potential treatment for Huntington’s disease
has shown positive results in the first series of
mouse trials and is currently being tested in a
different mouse model of the disease to see if it
can protect brain cells from degenerating.
Protein misfolding is a central concept in all the
neurodegenerative diseases. In Parkinson’s and
Lewy Body disease, the protein alpha-synuclein misfolds and forms clumps. Tiago Outeiro, PhD,
working in Dr. Brad Hyman’s laboratory, has collaborated with Dr. Alex Kazantsev to screen for
drugs that affect the toxic folding and clumping of this protein in brain cells. They discovered a
promising compound that seems to work in both Huntington’s disease cells and even more
powerfully in Parkinson’s disease cells. Work is ongoing to refine this compound and seek even
stronger agents with the same effects.
In Alzheimer’s disease, cholesterol has been implicated as contributing to the accumulation of
A-beta, the toxic protein piece that forms plaques in the brain. A two part study led by Dora
Kovacs, PhD is currently underway at MIND to see if compounds that prevent or decrease the
production of A-beta by altering cholesterol production in the brain could be effective. These
drugs, called ACAT inhibitors, were originally developed for heart disease. An initial study showed
that one type of inhibitor reduced plaques in the AD mouse brain. Currently underway is a
complementary study with another ACAT inhibitor that has previously reached phase III trials
(found to be safe) in humans. If it is shown to be effective in mice, it could go forward to human
trials quickly. This project is generously supported by the Cure Alzheimer’s Fund.
Drug discovery efforts in Dr. Robert Brown’s laboratory received an important boost recently
with the award of a federal grant to enhance the laboratory’s impressive array of drug screening
projects for ALS and other neuromuscular disorders. This grant builds on Dr. Brown’s
expertise in this area and supports collaboration with former MIND investigators Dr. Piera
Pasinelli and Dr. Davide Trotti, now both at Thomas Jefferson University. Dr. Brown will utilize
their cell-based assays that mimic ALS in the Petri dish to screen thousands of compounds that
have the potential to be developed into drugs for ALS. Compounds which show promise can then
be enhanced and modified for use in mouse trials.
An enzyme known to be critical for the repair of damaged cells and the maintenance of cellular
energy has been identified as a target for new strategies to treat Huntington's, Parkinson’s,
and other disorders characterized by low cellular energy. This enzyme is known as PARP1 and
Dr. Alex Kazantsev has discovered a small molecule compound that inhibits its activity and thereby can protect both HD-affected cells and PD cells from death in laboratory test tube.This small
molecule has the potential to be developed into a drug not only for HD and PD but could be
beneficial for cancer and over twenty other human disorders. Further work is currently underway
to refine this molecule, strengthen it, and prepare for animal testing.
MESSAGE FROM DR.YOUNG
MIND is five years old and we
have so much to celebrate.
Amazingly, both our research
budget and our staff has doubled.
Our resulting tight quarters,
while sometimes inconvenient,
also encourage scientists to bump
into each other, share ideas, and
initiate fruitful collaborations. This
review highlights some work, but
there is not enough space to
describe all the progress or the
enthusiasm that is so tangible
when I walk around the institute.
Our scientists are not locked in
isolated laboratories—every
advance in the lab must answer
the question—how could this
new idea help patients today?
As a result, MIND has turned
many breakthroughs into drug
discovery projects, finding seven
compounds that have the
potential to be developed into
drugs, surpassing the results of
some large biotech companies.
How do we do it? Interaction,
innovation, intuition, and—most
importantly—investments from
committed patients and friends
who believe that we can and
must cure these diseases.Thank
you for that support, and please
continue to invest in our work,
because we need it now more
than ever.
Anne Young, MD, PhD
Chief of Neurology,
Scientific Director, MIND
CLINICAL TRIALS BRING MIND’S SCIENCE
Adenosine A 2A Receptors and
Parkinson’s Disease—Coffee
Provides Clues
Intriguing data from
epidemiological studies
have shown that that
consumption of coffee
and other forms of caffeine is associated with a
lower risk of developing
Parkinson’s disease (PD).
Michael Schwarzschild,
MD, PhD has investigated
how caffeine’s effects on
specific brain cell receptors may help protect cells. Receptors are molecules on the surface of the
cell that can receive signals from other cells. Adenosine A2A receptors,
which are plentiful in the region of the brain that is affected in Parkinson’s
disease, are involved in controlling movement and are sensitive to caffeine.
Research suggests that drugs that block the receptors can partially
reverse motor deficits.
Dr. Schwarzschild plays a leading role in investigating how all this information
may inform the development of new PD treatments. In 2006, 200 neuroscientists and physicians from around the world, as well as pharmaceutical
and biotechnology industry experts, convened at Mass General to share
research. The conference—Targeting Adenosine A2A Receptors in
Parkinson’s Disease and other CNS Disorders—was co-chaired by Dr.
Schwarzschild and covered new basic science advances, clinical trials of
drugs that block the receptors, and strategies to accelerate the translation
of newfound knowledge into viable therapies for PD.
Dr. Schwarzschild is also interested in how A2A receptors may be manipulated to reduce dyskinesia—the excessive movements that can be a disabling
side effect of long term treatment with L-dopa, the mainstay therapy for
PD. His lab has shown that blocking adenosine receptors can prevent
dyskinesia-like activity in parkinsonian mice that have been treated with
L-dopa. His research group has also examined the potential interactions
between A2A receptors and estrogen, because epidemiological studies
have shown that caffeine is linked to a reduced risk of PD only in those
women who have not taken post-menopausal estrogen replacement
therapy. “We are fortunate to have collaborations that allow us to study
large populations over time to see what may contribute to developing
PD—this rich and varied information provides clues to pursue in the
laboratory and eventually will lead to medicines that work in patients,”
said Dr. Schwarzschild.
Industry Partnerships
Accelerate Treatment
One of the goals of the creation of MIND five years
ago was to enlist interest from pharmaceutical and
biotech companies to work on these difficult diseases, especially those like HD and ALS which are
“orphan diseases”—affecting relatively few patients.
Our goal became a reality this year when MIND
signed a groundbreaking agreement with Novartis, a
world leader in drug discovery. The agreement will
bring together teams from MIND, MIT and Novartis
to work collaboratively on Huntington’s disease
therapies. It is the first time a large pharmaceutical
company has made a substantial commitment to
tackle Huntington’s disease, bringing intellectual, scientific, and financial resources to the research, including
Novartis’s formidable drug compound library. All the
partners believe the collaboration will accelerate the
process of finding and testing new drugs.
"Our goal is to help patients now and in the future.
When the molecular basis of disease comes into focus,
as for HD, we ask how readily we can gain a therapeutic foothold. In this case, the discoveries of colleagues
in MIND and MIT provide a fantastic basis for potential
stated Mark Fishman, MD, President of the Novartis
Institutes for BioMedical Research.
MIND’s Day Laboratory for Neuromuscular Research
has joined forces with the newly created AviTx to
develop novel approaches to ALS treatment. This
company was created by Avi Kremer, a Harvard
Business School student who was diagnosed with ALS
in 2004. Having raised more than $2 million for ALS
research, he has turned his attention to biotech
approaches for delivery of therapeutics to the brain,
which is a considerable challenge in all brain diseases
since it is difficult to get compounds to cross the
blood-brain barrier. Dr. Jonathan Francis is working
with Dr. Robert Brown, Director of the Day Lab, and
AviTx to examine whether a non-toxic fragment of
tetanus can improve delivery of neuronal growth
factors to the particular nerve cells that are dying in
ALS. If this approach is successful in ALS, it could be
used in other diseases that also require drug delivery
to the brain.
The mission of MIND is to accelerate the translation of
basic research into the development of drugs to help
patients. To further this goal, MGH has created a
Neurology Clinical Trials Unit led by Merit Cudkowicz,
MD and Steven Greenberg, MD, PhD to assist in the
design and implementation of clinical trials as well as
the education and recruitment of patient subjects.
Concepts that have been proven at the molecular level in
the test tube undergo an arduous process to determine
if a research advance could be transformed into new drug
discovery. Once a molecule is identified that protects cells
in the test tube, it must undergo extensive modification
and re-testing to determine whether the intended effects
are actually attributable to the drug and reproducible
in various models—which could include cells, fruit
flies, and worms. Compounds that pass these hurdles
can then be tested in mice which display symptoms of the
various neurodegenerative diseases. Drugs that improve
functioning and prolong survival in several different trials
in mice are then brought forward to human clinical trials.
Human clinical trials go through three separate phases
to assess a drug’s effectiveness, compare it against existing
treatments and identify all side effects in increasingly
larger and more diverse patient populations. In order
to expedite clinical trials and assure unbiased results,
MGH neurologists are members of several nonprofit,
academic clinical research groups which can enroll large
populations and are dedicated to the dissemination of
both positive and negative results of clinical studies.
Currently, many clinical trials are underway or will enroll
soon at MGH, all of which had their beginnings in
laboratory benches at MIND or at other institutions
around the world, for example:
• Antibiotics are being tested for their neuroprotective
properties in ALS and HD;
• The nutritional supplements coenzyme Q10 and
creatine are being tested for their ability to improve
cellular energy and therefore brain cell function in
HD, PD and ALS;
TO THE
P AT I E N T
“I participate in
clinical trials because I
want to be part of moving
treatment forward, plus
I learn so much every
time I go in—the flow of
information is great.
When I saw the research
labs at MIND I was overwhelmed and amazed at
everything going on and
proud to be part of it.”
Todd Bliss, patient at MGH
• An antibody treatment that triggers a person’s immune
system to clear toxic protein from the brain is being
tested for Alzheimer’s disease;
• Two drugs that stop protein aggregation are being
tested in ALS;
• An experimental drug that acts as a dopamine agonist
is being tested for Parkinson’s disease.
In addition to these and other drug studies, MGH
researchers are also invested in finding biomarkers for
neurodegenerative diseases. These important studies
look for molecules in the blood or spinal fluid and
changes in brain imaging to find ways to diagnose
diseases earlier and track the progression accurately
with objective measures.
For more information on clinical trials
please talk to your Mass General neurologist
or email the Neurology Clinical Trials Unit at
[email protected].
MassGeneral Institute for Neurodegenerative Disease
114 16th Street
Charlestown, Massachusetts 02129
617.726.1278
email: [email protected]
www.mghmind.org
MASSACHUSETTS ALZHEIMER'S
DISEASE RESEARCH CENTER
JAN 2007
RESEARCH
R E V I E W
Collaborating for Cures
Reaching Drug Discovery Milestones in Alzheimer’s,
ALS, Huntington’s, and Parkinson’s Disease
Dr. Anne Young and patient Todd Bliss in the MIND
drug discovery laboratory.
Three years of hard work perfecting drug discovery
techniques at the MassGeneral Institute for
Neurodegenerative Disease has begun to pay off
with several promising projects. The protein
clearance drug “C2-8” that was discovered last year
as a potential treatment for Huntington’s disease
has shown positive results in the first series of
mouse trials and is currently being tested in a
different mouse model of the disease to see if it
can protect brain cells from degenerating.
Protein misfolding is a central concept in all the
neurodegenerative diseases. In Parkinson’s and
Lewy Body disease, the protein alpha-synuclein misfolds and forms clumps. Tiago Outeiro, PhD,
working in Dr. Brad Hyman’s laboratory, has collaborated with Dr. Alex Kazantsev to screen for
drugs that affect the toxic folding and clumping of this protein in brain cells. They discovered a
promising compound that seems to work in both Huntington’s disease cells and even more
powerfully in Parkinson’s disease cells. Work is ongoing to refine this compound and seek even
stronger agents with the same effects.
In Alzheimer’s disease, cholesterol has been implicated as contributing to the accumulation of
A-beta, the toxic protein piece that forms plaques in the brain. A two part study led by Dora
Kovacs, PhD is currently underway at MIND to see if compounds that prevent or decrease the
production of A-beta by altering cholesterol production in the brain could be effective. These
drugs, called ACAT inhibitors, were originally developed for heart disease. An initial study showed
that one type of inhibitor reduced plaques in the AD mouse brain. Currently underway is a
complementary study with another ACAT inhibitor that has previously reached phase III trials
(found to be safe) in humans. If it is shown to be effective in mice, it could go forward to human
trials quickly. This project is generously supported by the Cure Alzheimer’s Fund.
Drug discovery efforts in Dr. Robert Brown’s laboratory received an important boost recently
with the award of a federal grant to enhance the laboratory’s impressive array of drug screening
projects for ALS and other neuromuscular disorders. This grant builds on Dr. Brown’s
expertise in this area and supports collaboration with former MIND investigators Dr. Piera
Pasinelli and Dr. Davide Trotti, now both at Thomas Jefferson University. Dr. Brown will utilize
their cell-based assays that mimic ALS in the Petri dish to screen thousands of compounds that
have the potential to be developed into drugs for ALS. Compounds which show promise can then
be enhanced and modified for use in mouse trials.
An enzyme known to be critical for the repair of damaged cells and the maintenance of cellular
energy has been identified as a target for new strategies to treat Huntington's, Parkinson’s,
and other disorders characterized by low cellular energy. This enzyme is known as PARP1 and
Dr. Alex Kazantsev has discovered a small molecule compound that inhibits its activity and thereby can protect both HD-affected cells and PD cells from death in laboratory test tube.This small
molecule has the potential to be developed into a drug not only for HD and PD but could be
beneficial for cancer and over twenty other human disorders. Further work is currently underway
to refine this molecule, strengthen it, and prepare for animal testing.
MESSAGE FROM DR.YOUNG
MIND is five years old and we
have so much to celebrate.
Amazingly, both our research
budget and our staff has doubled.
Our resulting tight quarters,
while sometimes inconvenient,
also encourage scientists to bump
into each other, share ideas, and
initiate fruitful collaborations. This
review highlights some work, but
there is not enough space to
describe all the progress or the
enthusiasm that is so tangible
when I walk around the institute.
Our scientists are not locked in
isolated laboratories—every
advance in the lab must answer
the question—how could this
new idea help patients today?
As a result, MIND has turned
many breakthroughs into drug
discovery projects, finding seven
compounds that have the
potential to be developed into
drugs, surpassing the results of
some large biotech companies.
How do we do it? Interaction,
innovation, intuition, and—most
importantly—investments from
committed patients and friends
who believe that we can and
must cure these diseases.Thank
you for that support, and please
continue to invest in our work,
because we need it now more
than ever.
Anne Young, MD, PhD
Chief of Neurology,
Scientific Director, MIND