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http://friedreichscientificnews.blogspot.com/2010/01/flavin-adenine-dinucleotide-rescues.html
Saturday, January 23, 2010
Flavin Adenine Dinucleotide Rescues the Phenotype of Frataxin Deficiency
Gonzalez-Cabo P, Ros S, Palau F (2010) Flavin Adenine Dinucleotide
Rescues the Phenotype of Frataxin Deficiency. PLoS ONE 5(1): e8872. doi:10.1371/journal.pone.0008872
OPEN ACCESS
Pilar Gonzalez-Cabo1,2#, Sheila Ros1,2#¤, Francesc Palau1,2*
1 Laboratory of Genetics and Molecular Medicine, Instituto de
Biomedicina de Valencia, CSIC, Valencia, Spain, 2 CIBER de Enfermedades
Raras (CIBERER), Valencia, Spain
Abstract
Background
Friedreich ataxia is a neurodegenerative disease caused by the lack of
frataxin, a mitochondrial protein. We previously demonstrated that
frataxin interacts with complex II subunits of the electronic transport
chain (ETC) and putative electronic transfer flavoproteins, suggesting
that frataxin could participate in the oxidative phosphorylation.
Methods and Findings
Here we have investigated the effect of riboflavin and its cofactors
flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) in
Saccharomyces cerevisiae and Caenorhabditis elegans models of frataxin
deficiency. We used a S. cerevisiae strain deleted for the yfh1 gene
obtained by homologous recombination and we assessed growth in
fermentable and non-fermentable cultures supplemented with either
riboflavin or its derivates. Experiments with C. elegans were performed
in transient knock-down worms (frh-1[RNAi]) generated by microinjection
of dsRNA frh-1 into the gonads of young worms. We observed that FAD
rescues the phenotype of both defective organisms. We show that cell
growth and enzymatic activities of the ETC complexes and ATP production
of yfh1Δ cells were improved by FAD supplementation. Moreover, FAD also
improved lifespan and other physiological parameters in the C. elegans
knock-down model for frataxin.
Conclusions/Significance
We propose that rescue of frataxin deficiency by FAD supplementation
could be explained by an improvement in mitochondrial respiration. We
suggest that riboflavin may be useful in the treatment of Friedreich
ataxia.
http://www.babelfamily.org/en/latestataxianews/682-excess-dna-damage-found-in-cells-of-patients-with-friedreichs-ataxia
Excess DNA damage found in cells of patients with Friedreich's ataxia
Public release date: 14-Jan-2010
Contact: Anita Srikameswaran
SrikamAV@upmc.edu CLOAKING
412-578-9193
University of Pittsburgh Schools of the Health Sciences
Biomarkers, new treatments possible for Friedreich's ataxia
PITTSBURGH, Jan. 14 – Elevated levels of DNA damage have for the first
time been found in the cellular mitochondria and nuclei of patients with
the inherited, progressive nervous system disease called Friedreich's
ataxia (FRDA), says a multicenter research team led by an expert from
the University of Pittsburgh Cancer Institute (UPCI). The findings,
described today in PLoS Genetics, shed light on the molecular
abnormalities that lead to the disease, as well as point the way to new
therapeutic approaches and the development of biomarker blood tests to
track its progression.
"In FRDA, mutations in the gene frataxin reduce production of a protein
that plays a role in keeping iron levels in balance within
mitochondria," explained Bennett Van Houten, Ph.D., Richard M. Cyert
Professor of Molecular Oncology and leader of the molecular and cellular
cancer biology program at UPCI, and professor, Department of
Pharmacology and Chemical Biology, University of Pittsburgh School of
Medicine. "Frataxin binds iron and helps build iron-sulfur clusters,
which are important constituents of cellular proteins."
"While iron is what allows blood cells to carry oxygen, too much iron is
toxic to the body," said Astrid C. Haugen, lead author and program
analyst at the National Institute of Environmental Health Sciences
(NIEHS), part of the National Institutes of Health (NIH). "Friedreich's
ataxia leads to iron overload, setting the stage for cumulative DNA
damage that eventually affects patients' nerve and muscle cells."
http://www.frcblog.com/2010/01/als-clinical-trial-approved-with-adult-stem-cells/
ALS Clinical Trial Approved with Adult Stem Cells
by David Prentice
January 14, 2010
A biotech company in Louisiana, TCA Cellular Therapy, has received FDA
approval to begin a Phase I clinical trial with its adult stem cell
protocol to treat Amyotrophic Lateral Sclerosis (ALS, Lou Gehrig’s
disease). ALS is a terrible neurological disease that afflicts
approximately 30,000 Americans; life expectancy once diagnosed is 2-5
years. Adult stem cells will be taken from the patient’s bone marrow in
an outpatient procedure, processed in the company’s lab, and
administered to the patient by spinal tap.
Keep in mind this is only approval to begin the trial, no patient
results are yet available, as no patients have yet even been treated in
this trial. But it is the first adult stem cell patient trial for ALS
approved in the United States.
Previously, Italian scientists Mazzini and Fagioli have done several
clinical trials using adult mesenchymal stem cells, with promising
results. They have published clinical trial results in 2006, in 2008,
and in 2009, as well as a recent review paper on the subject.
Adult stem cells continue to show real progress and hope for patients.
http://www.ncbi.nlm.nih.gov/pubmed/20069237?dopt=Abstract
Autosomal recessive ataxias: 20 types, and counting.
Embiruçu EK, Martyn ML, Schlesinger D, Kok F.
Outpatient Neurogenetics Clinic, Hospital das Clínicas, School of
Medicine, University of São Paulo, São Paulo, SP, Brazil.
More than 140 years after the first description of Friedreich ataxia,
autosomal recessive ataxias have become one of the more complex fields
in neurogenetics. Currently this group of diseases contains more than 20
clinical entities and an even larger number of associated genes. Some
disorders are very rare, restricted to isolated populations, and others
are found worldwide. An expressive number of recessive ataxias are
treatable, and responsibility for an accurate diagnosis is high. The
purpose of this review is to update the practitioner on clinical and
pathophysiological aspects of these disorders and to present an
algorithm to guide the diagnosis.
http://money.cnn.com/news/newsfeeds/articles/globenewswire/181579.htm
Penwest Announces Initiation of Phase IIa Clinical Trial of A0001 in
Patients With Friedreich's Ataxia
January 11, 2010: 08:00 AM ET
PATTERSON, N.Y., Jan. 11, 2010 (GLOBE NEWSWIRE) -- Penwest
Pharmaceuticals Co. (Nasdaq:PPCO) today announced that it initiated a
Phase IIa clinical trial for A0001 in December and that the screening of
patients is underway. The study is being conducted at The Children's
Hospital of Philadelphia in patients with Friedreich's Ataxia (FA).
The primary objective of this study is to investigate whether treatment
with A0001 has a discernible impact on various functional, biochemical
and subject/clinician-rated scales relevant in the treatment of FA. The
Phase IIa clinical trial is a double-blind, randomized,
placebo-controlled trial that includes a high and low dose of A0001 and
a placebo. Penwest plans to enroll approximately 42 patients with a 2:1
randomization of drug to placebo. The patients will be dosed for 28
days. The Company expects data from this trial in the third quarter of
this year.
The Friedreich's Ataxia Research Alliance (FARA) is helping to enroll
patients for this study by utilizing its patient registry. Ronald J.
Bartek, FARA's President and Co-Founder, said, "The Friedreich's ataxia
community is excited that A0001 is ready to be dosed in our patients. We
believe the science behind the molecule is very interesting and that
A0001 could be an important therapy for FA patients. FARA has been
helping support the development of A0001 for a number of years and is
continuing to assist its development partners at Penwest by working with
the patient community to ensure the trial enrolls rapidly."
Jennifer L. Good, Penwest's President and CEO, said, "We are very
pleased to be advancing A0001 into a proof of concept trial in patients.
There is a significant unmet medical need in Friedreich's ataxia and we
are hopeful that A0001 can provide an important treatment option for
these patients."
About A0001
A0001, or alpha-tocopherol quinone, is a coenzyme Q10 analog
demonstrated to improve mitochondrial function in-vitro. Penwest
believes that impairment of mitochondrial function is a key component of
the diseases that it plans to target with A0001, and that enhancing
mitochondrial function may provide substantial clinical benefit to
patients. The Company exclusively licensed A0001 from Edison
Pharmaceuticals, a privately-held biopharmaceutical company
headquartered in San Jose, CA.
About Friedreich's Ataxia
Friedreich's Ataxia (FA) is a debilitating, life-shortening,
degenerative neuro-muscular disorder. About one in 50,000 people in the
United States have FA. Onset of symptoms can vary from childhood to
adulthood. FA patients have gene mutations that limit the production of
a protein called frataxin. Frataxin is known to be an important protein
that functions in the mitochondria (the energy producing factories) of
the cell. Frataxin helps to move iron and is involved with the formation
of iron-sulfur clusters, which are necessary components in the function
of the mitochondria and thus energy production. It is also known that
specific nerve cells (neurons) degenerate in people with FA, and this is
directly manifested in the symptoms of the disease.
The signs and symptoms of FA include: loss of coordination (ataxia) in
the arms and legs, fatigue, energy deprivation, muscle loss, vision
impairment, hearing loss, slurred speech, aggressive scoliosis
(curvature of the spine), diabetes mellitus, and a serious heart
condition (enlarged heart - hypertrophic cardiomyopathy).
About Penwest Pharmaceuticals
Penwest is a drug development company focused on identifying and
developing products that address unmet medical needs, primarily for rare
disorders of the nervous system. Penwest is currently developing A0001,
or alpha tocopherol quinone, a coenzyme Q10 analog demonstrated to
improve mitochondrial function in-vitro. Penwest is also applying its
drug delivery technologies and drug formulation expertise to the
formulation of our collaborators' product candidates under licensing
collaborations.
Penwest Forward-Looking Statements
The matters discussed herein contain forward-looking statements for
purposes of the safe harbor provisions under The Private Securities
Litigation Reform Act of 1995 that involve risks and uncertainties,
which may cause the actual results in future periods to be materially
different from any future performance suggested herein. For this
purpose, any statements contained herein that are not statements of
historical fact may be deemed to be forward-looking statements. Without
limiting the foregoing, the words, "believes," "anticipates," "plans,"
"expects," "intends," "potential," "appears," "estimates," "projects,"
"targets," "may," "could," and similar expressions are intended to
identify forward-looking statements. Important factors that could cause
results to differ materially include the following: risks relating to
the commercial success of Opana ER, including our reliance on Endo
Pharmaceuticals Inc. for the commercial success of Opana ER and risks of
generic competition; the need for capital; regulatory risks relating to
drugs in development, including the timing and outcome of regulatory
submissions and regulatory actions with respect to A0001; uncertainty of
success of collaborations; the timing of clinical trials, such as the
Phase IIa clinical trial referenced above; whether the results of
clinical trials will be indicative of the results of future clinical
trials and will warrant further clinical trials, warrant submission of
an application for regulatory approval of, or warrant the regulatory
approval of, the product that is the subject of the trial; whether the
patents and patent applications owned by us will protect the Company's
products and technology; actual and potential competition; and other
risks as set forth under the caption Risk Factors in Penwest's Quarterly
Report on Form 10-Q filed with the Securities and Exchange Commission on
November 9, 2009, which risk factors are incorporated herein by
reference.
The forward-looking statements contained in this press release speak
only as of the date of the statements made. Penwest disclaims any
intention or obligation to update any forward-looking statements, and
these statements should not be relied upon as representing the Company's
estimates or views as of any date subsequent to the date of this
release.
TIMERx is a registered trademark of Penwest. All other trademarks
referenced herein are the property of their respective owners.
CONTACT: Penwest Pharmaceuticals Co.
Investors:
Jennifer Good
(845) 878-8401
(877) 736-9378
Kekst and Company
Media:
John Patteson
(212) 521-4800
http://www3.interscience.wiley.com/journal/123234525/abstract?CRETRY=1&SRETRY=0
Measuring the rate of progression in Friedreich ataxia: Implications
for clinical trial design
Lisa S. Friedman, BS 1 2 3, Jennifer M. Farmer, MS 1 2 3, Susan Perlman,
MD 4, George Wilmot, MD, PhD 5, Christopher M. Gomez, MD PhD 6 7, Khalaf
O. Bushara, MD 6, Katherine D. Mathews, MD 8, S. H. Subramony, MD 9 10,
Tetsuo Ashizawa, MD 9 11, Laura J. Balcer, MD, MSCE 1, Robert B. Wilson,
MD, PhD 12, David R. Lynch 1 2 3 *
1Department of Neurology, School of Medicine, University of
Pennsylvania, Philadelphia, Pennsylvania
2Department of Pediatrics, School of Medicine, University of
Pennsylvania, Philadelphia, Pennsylvania
3Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
4Department of Neurology, David Geffen School of Medicine at the
University of California, Los Angeles, Los Angeles, California, USA
5Department of Neurology, Emory University, Atlanta, Georgia, USA
6Department of Neurology, University of Minnesota, Minneapolis,
Minnesota, USA
7Department of Neurology, University of Chicago, Chicago, Illinois, USA
8Departments of Neurology and Pediatrics, University of Iowa, Iowa City,
Iowa, USA
9Department of Neurology, University of Texas Medical Branch, Galveston,
Texas, USA
10Department of Neurology, University of Mississippi, Jackson,
Mississippi, USA
11Department of Neurology, University of Florida, Gainesville, Florida,
USA
12Department of Pathology and Laboratory Medicine, School of Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania
email: David R. Lynch (lynchd@mail.med.upenn.edu)
*Correspondence to David R. Lynch, Department of Neurology, Abramson
Research Center, Children's Hospital of Philadelphia, Room 502, 3615
Civic Center Blvd, Philadelphia 19104, PA
Potential conflict of interest: The authors report no conflict of
interest related to this study.
Funded by:
Friedreich Ataxia Research Alliance
Muscular Dystrophy Association
Keywords
ataxia • natural history study • clinical neurology examination •
mitochondrial disorder • trinucleotide repeat disease
Abstract
Friedreich ataxia is an autosomal recessive neurodegenerative disorder
characterized by ataxia of all four limbs, dysarthria, and arreflexia. A
variety of measures are currently used to quantify disease progression,
including the Friedreich Ataxia Rating Scale, examiner-rated functional
disability scales, self-reported activities of daily living and
performance measures such as the timed 25-foot walk, 9-hole pegboard
test, PATA speech test, and low-contrast letter acuity vision charts.
This study examines the rate of disease progression over one and two
years in a cohort of 236 Friedreich ataxia patients using these scales
and performance measure composites. The Friedreich Ataxia Rating Scale
and performance-measure composites captured disease progression, with a
greater sensitivity to change over 2 years than over 1 year. The
measures differed in their sensitivity to change and in possible bias.
These results help to establish norms for progression in FRDA that can
be useful in measuring the long-term success of therapeutic agents and
defining sample-size calculations for double-blind clinical trials. ©
2009 Movement Disorder Society
In 2008, Dr. Payne was the first recipient of
the joint American Heart Association/FARA Friedreich’s
ataxia Award. From FARA Update 2010
Can you tell us a bit about your current research into TATFrataxin.
What is TAT-Frataxin?
TAT-Frataxin is a protein consisting of normal human frataxin
attached to a short protein called TAT. This type of artificially
created protein is called a ”fusion protein”and means that the
genes encoding two separate proteins have been attached
to each other to make a single protein, TAT-Frataxin in this
case. The TAT protein is a short peptide that has the ability
to move across both cell (cell penetrant) and mitochondrial
membranes and pull a larger protein with it inside the cell.
So, as a fusion protein, TAT-Frataxin has two functions: the
TAT pulls the normal human frataxin protein into the cell
and mitochondria, and the frataxin is recognized by the
mitochondria and functions as normal frataxin protein.
Why is Frataxin important in FA?
Frataxin is the protein that is missing in Friedreich’s ataxia.
The gene encoding this protein is defective and thus, no
frataxin is produced or else it is produced in such low
amounts that it can’t do its job effectively. Studies have
shown that if the cell ever has frataxin, it will handle this
protein appropriately and has normal function. Frataxin is
an iron binding protein that functions inside of mitochondria
to bind and present iron to other protein complexes. In its
absence, these other critical enzymes and proteins cannot
function effectively. As a result, the mitochondria eventually
stop producing energy and the cell no longer functions
normally. Loss of mitochondrial function is critical for tissues,
such as brain and heart, which use lots of energy.
Your early results have been promising.
What has your research into TAT-Frataxin shown so far?
We are excited about our findings. To date, we have
been able to show that a TAT-Frataxin protein will move
across the cell membrane into mitochondria. For cells
in culture from patients with FA, we’ve been able to
show that treating these cells with TAT-Frataxin restores
their resistance to an oxidant stress from iron exposure.
For the Friedreich’s ataxia mouse model from Helene
Puccio, we’ve been able to partially rescue the animals
with TAT-Frataxin and markedly extend their lifespan.
They have better heart function. This is very important
because these animals represent the most severe
phenotype of FA in that they are completely lacking
frataxin expression in certain tissues. These findings
have encouraged us to pursue TAT-Frataxin to see if we
can optimize its performance and function.
What is your goal with your TAT-Frataxin research?
There are two goals for this research: 1) Develop a
therapy for Friedreich’s ataxia (FA). We are hopeful that
we can develop TAT-Frataxin, or a variant of this protein,
to function effectively as a new drug to treat patients
with FA. 2) Take the lessons we learn from working
with TAT-Frataxin and expand this technology to other
mitochondrial diseases. This will help us develop new
drugs and therapies for other diseases, and discover
new knowledge about mitochondria.
Your research has been funded by Shire Human
Genetics, Inc. Is this research a priority for the
company?
Yes, they are deeply committed to this approach and
this is a priority for this company. They have a mission to
develop therapies and cures for rare and difficult diseases
and have been successful in the past.
What is the timeline before TAT-Frataxin could be in
patient clinical trials?
This is hard to guess at because there are so many
variables and experiments that have yet to be done. If
results from additional animal and laboratory studies
progress as hoped, then it is quite possible that a TATFrataxin
molecule could move into pre-clinical studies
within two years. Phase I studies would follow after
these were completed and had been approved by the
FDA. At the earliest, five years would be realistic for
significant clinical trials.
Friedreich's Ataxia Research Alliance (FARA)
P. O. Box 1537 Springfield, VA 22151
Tel (703) 426-1576; http://www.CureFA.org
FA Patient Registry: http://curefa.org/registry/
E-Bulletin Sign-up: http://curefa.org/news/index.asp
VIEW THE LATEST NEWSLETTER, The Advocate
http://www.curefa.org/newsletter/newsletter_2009-2010_winter.pdf
http://www.babelfamily.org/en/latestataxianews/671-splitting-fluorescent-protein-helps-image-clusters-in-live-cells-
Splitting fluorescent protein helps image clusters in live cells
December 25, 2009 (Nanowerk News). Half a protein is better than none,
and in this case, it's way better than a whole one. A Rice University
lab has discovered that dividing a particular fluorescent protein and
using it as a tag is handy for analyzing the workings of live cells,
particularly in the way they employ iron-sulfur clusters. Iron and
sulfur in just the right amounts are critical to good health. They're in
the food people eat and vitamins they take every day, but having too
much or too little in the cells can cause serious problems. Iron-sulfur
clusters are molecules with as few as four atoms. They are manufactured
and regulated by proteins in living cells, and their role is a fairly
recent field of study for researchers interested in Friedreich's ataxia,
sideroblastic anemia and myopathy, diseases caused by defects in
proteins.
But until now, there's been no way to look at such "metalloclusters" in
living cells. Jonathan Silberg, an assistant professor of biochemistry
and cell biology at Rice, has been studying the mysteries of these
molecules for years. He has come up with a way to see what they're doing
in living cells. Silberg and his team published a paper in the December
edition of Chemistry & Biology that details a new technique for imaging
clusters that involves attaching them, through an intermediary, to
fluorescent fragments of protein. That intermediary is a human protein
called GRX2, a glutaredoxin that helps cells deal with oxidative damage
on other proteins. Its activity can be switched off in test tubes by
association with an iron-sulfur cluster. The team had already proved
that GRX2 would still bond with iron-sulfur clusters even when tagged
with a green fluorescent protein; this makes it useful for in vitro
studies, but the fluorescence wasn't strong enough to be seen in living
cells.
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