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The scandal of clinical trial data loss is eroding the fundamentals of evidence-based research and clinical medicine.


Before you right this post off as the stuff of conspiracy theories, fear-mongering, and 'alternative world views' consider that this view is shared by the likes of the FDA, the International Committee of Medical Journal Editors, the Cochrane Collaboration, and researchers at institutions like Johns Hopkins School of Medicine.


Here's the underlying premise as succinctly described by author Ben Goldacre:

"Drugs are tested by the people who manufacture them, in poorly designed trials, on hopelessly small numbers of weird, unrepresentative patients, and analysed using techniques that are flawed by design, in such a way that they exaggerate the benefits of treatments. Unsurprisingly, these trials tend to produce results that favour the manufacturer.

When trials throw up results that companies don't like, they are perfectly entitled to hide them from doctors and patients, so we only ever see a distorted picture of any drug's true effects. Regulators see most of the trial data, but only from early on in a drug's life, and even then they don't give this data to doctors or patients, or even to other parts of government. This distorted evidence is then communicated and applied in a distorted fashion."

Authors M. Todwin and J. Abramson summarize it thusly:

"Trials with positive results generally are published more frequently than studies that conclude that a new drug poses greater risks or is no more effective than standard therapy or a placebo. Furthermore, some articles may distort trial findings by omitting important data or by modifying prespecified outcome measures. Lack of access to detailed information about clinical trials can undermine the integrity of medical knowledge."

Here is a great list of very recent resources that may convince you of the merits of this concern:

• What doctors don't know about the drugs they prescribe (2012: TED video)
• The drugs don't work: a modern medical scandal (2012: The Guardian)
• Clinical Trial Data as a Public Good (2012: JAMA [subscription req'd])
• Registering Clinical Trial Results. The Next Step (2010: JAMA [subscription req'd])
• The Imperative to Share Clinical Study Reports: Recommendations from the Tamiflu Experience (2012: Plos Medicine)

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California's $3 billion stem cell
research effort today garnered a handsome dollop of favorable
national news coverage– a lengthy piece in Fortune magazine that
spoke of looming stem cell cures and the leading role of the state
stem cell agency.

“The citizens of California have
spoken. If my grandmother and I had the power to get the rest of the
country to follow, we would.”

“To be clear, the earliest stem cell
therapies are almost certainly years from distribution. But so much
progress has been made at venerable research institutions that it now
seems possible to honestly discuss the possibility of a new medical
paradigm emerging within a generation. Working primarily with rodents
in preclinical trials, MDs and Ph.D.s are making the paralyzed walk
and the impotent virile. A stem cell therapy for two types of macular
degeneration recently restored the vision of two women. Once they
were blind. Now they see!

“Some experts assert that AMD could
be eradicated within a decade. Other scientists are heralding a
drug-free fix for HIV/AIDS. Various forms of cancer, Parkinson's,
diabetes, heart disease, stroke, and ALS have already been eradicated
in mice. If such work translates to humans, it will represent the
type of platform advancement that comes along in medicine only once
in a lifetime or two. The effect on the economy would be substantial.
Champions of stem cell research say it would be on the order of the
Internet or even the transistor.”

“The obstacles along the road from
lab rat to human patients are many, of course, but the biggest by far
is money. With the dramatic events in the lab, you might think that a
gold rush would be under way. That's far from true. Long time
horizons, regulatory hurdles, huge R&D costs, public sentiment,
and political headwinds have all scared financiers. Wall Street isn't
interested in financing this particular dream. Most stem cell
companies that have dared go public are trading down 90% or more from
their IPOs. Sand Hill Road is AWOL. The National Venture Capital
Association doesn't even have a category to track stem cell
investments.”

“The $1.7 billion awarded so far has made one obvious mark on the state: a dozen gleaming research institutions. CIRM has proved adept at getting billionaires to donate funds to the cause.”

“Goodness, you're talking to the
wrong guy. Our donation had nothing to do with business.”

“For close to two hours, Grove argues
passionately about how the FDA is enabling predatory offshore
industries by impeding progress and the many reasons financiers want
no part of stem cells. "VCs aren't interested because it's a
shitty business," he says. Big Pharma? Forget it. CIRM? "There
are gleaming fucking buildings everywhere. That wasn't necessary."
When I press him to be constructive, he wearily offers one possible
solution. Rather than courting billionaires to put their names on
buildings, we need a system of targeted philanthropy in which the 99%
can sponsor the individual stem cell lines that matter to them.”

“It was clear during our talk that
Grove wants an economic model for stem cell research and development
to emerge, even if he's not willing to bet money on its happening.
And that puts him in good company.”

Source:
http://californiastemcellreport.blogspot.com/feeds/posts/default?alt=rss

The $700,000 study of the $3 billion
California stem cell agency is nearly concluded and is expected to be
released sometime in November.

“There will be no
further information-gathering meetings. The committee members have
finished drafting their report and it is now undergoing peer review.
Reviewers are anonymous to study staff and committee members; they
will be listed in the front matter of the report when it’s finished
and released.”

“Sponsors are not
treated as peer reviewers; that is, they’re not afforded an
opportunity to comment on IOM draft reports prior to public release.
IOM is aiming for a public release in November (the exact time frame
will hinge on the duration of the peer review, which is influenced by
people’s schedules and adherence to deadlines). IOM is looking at
options for how best to hold this release, whether there will be an
event of some sort. Once plans are set, they’ll be noted on the
project web pages and IOM will alert the various stakeholders and
interested parties of the plans. The study is moving along and we’re
looking forward to the report’s debut in the not too distant
future.”

Source:
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The location of the October meeting of
the governing board of the California stem cell agency has been
changed from Irvine to Burlingame, near San Francisco International
Airport, in an effort to save travel costs.  

Source:
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One of the lesser known activities of
the California stem cell agency is webinars that put researchers
together with the folks who make the federal decisions about whether
stem cell research will be turned into therapies.

“The FDA very graciously donates
their time to speak on these webinars because they too have pledged
to maintain an active dialogue with the industry and provide
education on their regulatory expectations for product development in
the regenerative medicine field. CIRM science officer Kevin
Whittlesey recently
wrote a paper with Celia Witten of the FDA about the role of the
FDA in reaching out to regenerative medicine community, including
webinars such as these. 

“In that paper they point out that
the communication goes both ways:

“'Appropriate regulation requires a
strong understanding of the latest scientific developments to meet
current and future regulatory needs and challenges.'

“So the FDA benefits by learning from
the other speakers in the webinar – what is the current state of
the technology, what are investigator’s current thoughts on best
practices and the latest research findings, etc. They also learn what
the industry is facing by listening to the questions asked and the
discussion of the challenges during the Q&A sessions. A group of
FDA employees attend each of these CIRM sponsored webinars, and the
wide variety of other workshops and meetings that CIRM hosts
throughout the year.”  

(Editor's note: An earlier version of this item incorrectly identified Cynthia Schaffer as Cynthia Adams.)

Source:
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The Sacramento Bee today published an article that reported that $1.5 billion, more than 90 percent of the amount dispensed by the California stem cell agency, has gone to institutions linked to past and present directors of the agency.

The piece was carried on the front page of the newspaper's Sunday Forum section and was written by David Jensen, publisher-editor of the California Stem Cell Report.

The text of the Forum article is below. The Bee also carried a chart listing the top 10 recipient institution. The full text of the comments from Alan Trounson, president of the California stem cell agency,  and two other persons quoted in the article can be found here.

Stem cell cash mostly aids directors' interests

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Here is the full text of comments made
by the California stem cell agency, Joe Mathews, co-author of
“California Crack-Up” and Bob Stern, former president of the
Center for Governmental Studies and co-author of the California
Political Reform Act, in connection with the Sept. 23, 2012, article
in The Sacramento Bee headlined “Stem Cell Cash Mostly Aids Directors' Interests.” The comments were abbreviated for
publication in The Bee because of newspaper space constraints.

“To make sure we do the best job of
managing taxpayer's money it's natural that we turn to people who
know most about stem cells and stem cell research. In fact, as the
state's own Little Hoover Commission reported in its analysis of
CIRM: “The fact that CIRM funding has gone largely to prestigious
California universities and research institutes is hardly surprising
and should be expected, given the goals of Proposition 71 and the
considerable expertise resident in these research centers.” But in
recruiting the best minds, we also adopt best practices to ensure
that there is no conflict of interest. Every board member has to
recuse themselves from voting on, or even being part of a discussion
on anything to do with their own institution, or to an institution or
company that they have any connections to. All this is done in
meetings that are open to the public. CIRM’s conflict of interest
rules have been subject to multiple reviews – by the Bureau of
State Audits, the Little Hoover Commission and the Controller – and
there is no evidence that any of CIRM’s funding decisions have been
driven by conflicts of interest. Indeed, CIRM rigorously enforces its
conflict of interest rules at each stage of the funding process to
ensure that all decisions are made on the merits of the proposal for
funding and not as a result of any conflicts of interest. 

“In addition all funding applications
are reviewed by an independent panel of scientists on our Grants
Working Groups, all of whom are out-of-state and meet strict conflict
of interest requirements, and it is their recommendations that help
guide the ICOC (CIRM governing board) on what to fund.”

“California ballot initiatives are a
terrible way to make public policy. And they are even worse as a
method for making scientific policy. 

“It's not merely that
this initiative was drafted in such a way as to benefit the
enterprises of its directors. It's that, under this initiative's own
provisions and the California constitution, it's so hard to change
Proposition 71 and fix what ails CIRM. Effectively, these provisions are
baked in, and nothing short of another vote of people can really make
the change. (Yes, there are provisions, as you know, that permit the
legislature by super-majority to do things, but supermajorities are
effectively out of reach in California). 

“Sadly, initiatives
like Proposition 71 are not uncommon. Many measures are drafted to benefit
the people who would support the measure, or oversee the program
established. This has been very common with bonds. Essentially, to
win the support of various groups whose money and backing is
important to passage of a bond, a sponsor of an initiative bond will
set up rules and include money specifically intended for each group.
This is a form of pay-to-play. Agree to back the initiative and
you're in. And it happens because there's no rule against it and
because passing initiatives in California require difficult,
expensive campaigns. 

“And this sort of thing will continue
to happen. There is no serious push to do anything about this.
Indeed, good government groups and reformers in California have
opposed changes to the initiative process -- because they want to use
the process for their own schemes.”

“It would have been better had
institutions receiving grants not to have had their representatives
on the board awarding grants. On the other hand, we want to have the
most knowledgeable people on the board overseeing this very important
program. The question: Were these people the only qualified ones to
sit on the board?”

Source:
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The Hindu

Safety in handling LMOs to feature in deliberations The Hindu Come Monday, over 2,000 delegates from more than 150 countries will converge in Hyderabad to discuss about ensuring safe transfer, handling and use of Living Modified Organisms (LMOs) resulting from the modern biotechnology. The LMOs are broadly ... Hyderabad to host bio-diversity conference from MondayDeccan Herald Convention on Biological Diversity meeting from tomorrowHindu Business Line AP to host UN biodiversity meet from Oct 1Firstpost all 20 news articles »

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By Ryan Flinn - 2012-09-28T20:12:41Z

Cytori Therapeutics Inc. (CYTX), a biotechnology company with $10 million in annual revenue, rose the most in about a year after the company won a $4.7 million U.S. government contract to develop a stem cell therapy to treat burns caused by thermal or radioactive bombs.

Cytori jumped 14 percent to $4.41 at the close in New York, the biggest single-day increase since October 2011. The shares of the San Diego-based company have doubled this year.

Were seeing a lot of momentum, Chief Executive Officer Christopher Calhoun said today in an interview with Bloomberg Television. This contract is one more major thing that we are delivering on, and there is more to come.

The two-year contract with the Department of Health and Human Services Biomedical Advanced Research and Development Authority may be worth $106 million over five years if certain milestones are met, Cytori said today in a statement. The company had a net loss last year of $32 million, according to data compiled by Bloomberg.

Cytoris experimental therapy takes adipose tissue, or body fat, from a patient and through its device separates the adult stem and regenerative cells before transferring them to a burn wound. Money from the contract will be used to develop the device and take it through the U.S. regulatory approval process with the Food and Drug Administration, Calhoun said.

These cells help to facilitate the healing of the injury, he said in a telephone interview earlier this week. They release growth factors that stimulate new blood flow.

Testing the technology in a clinical trial and getting approval may take five years, Calhoun said. The company is currently testing its therapy for other soft tissue damage, as well as cardiovascular disease.

Once approved, the device will be deployed in hospitals across the country, and can be used for routine burns as well as a treatment for patients in wake of a mass casualty event that could injure 10,000 people, Cytori said in the statement.

To contact the reporter on this story: Ryan Flinn in San Francisco at rflinn@bloomberg.net

View post:
Cytori’s Stem Cell Therapy for Burns Wins U.S. Contract

ROCKVILLE, Md., Sept. 27, 2012 /PRNewswire/ -- Neuralstem, Inc. (NYSE MKT: CUR) announced it has been approved to commence a clinical trial to treat motor deficits due to ischemic stroke with its spinal cord stem cells (NSI-566) at BaYi Brain Hospital, in Beijing, China, through its subsidiary, Neuralstem China (Suzhou Neuralstem Biopharmaceutical Company, Ltd.). The trial approval includes a combined phase I/II design and will test direct injections into the brain of NSI-566, the same cell product tested by Neuralstem in a recently-completed Phase IALS trial in the United States. The trial is expected to begin early next year. Ischemic strokes, the most common type of stroke, occur as a result of an obstruction within a blood vessel supplying blood to the brain. Post-stroke motor deficits include paralysis in arms and legs and can be permanent.

(Logo: http://photos.prnewswire.com/prnh/20061221/DCTH007LOGO )

"China is rapidly moving to become a prominent player in the field of stem cell transplantation and regenerative medicine," said Karl Johe PhD, Chairman of Neuralstem's Board of Directors and Chief Scientific Officer. "We are honored and excited to begin this process at BaYi Brain Hospital in Beijing, China. BaYi is one of the premier neurological hospitals in China, and we can assure all of our stake holders that the quality of the medical care and treatment our patients receive, as well as the entire protocol, will be the equal of any trial we do anywhere in the world, including our FDA-approved trial in the U.S."

"BaYi prides itself on its world class research capabilities," said Professor Xu RuXiang, President of the BaYi Hospital and principal investigator of the trial. "Chronic motor disorder from stroke is a serious public health issue for China, where we, as a population, now suffer over 2 million ischemic strokes per year.We are ready to be the world's first site for Neuralstem's cell therapy stroke trial and excited about its potential."

About the Trial

The trial is designed to enroll up to 118 patients who have suffered an ischemic stroke with chronic residual motor disorder with Neuralstem's NSI-566 cell line, 4-24 months post-stroke. The stem cell treatment involves a one-time treatment of intracerebral injections of Neuralstem's neural stem cells into the stroke area using well-accepted stereotactic injection procedures. The trial will be conducted in 2 parts. The first part of the study, Phase I, will be open-label and enroll up to 18 patients who will be assigned to 3 cohorts. Each of these will receive ascending doses of NSI-566 to define the maximal safe dose. The maximal safe dose defined in the first phase will be used to evaluate efficacy in the second part of the study, a Phase II/Proof-of-Concept study. This Phase will be a multi-site, randomized, controlled, single-blind study and enroll up to 100 randomized subjects. 50% of the subjects will receive a one-time treatment with the cells and physical therapy and the other 50% will receive only the physical therapy with no surgery. Outcome measures during the follow-up period in Phase II will be conducted in single-blinded manner. The combined study, including patient monitoring and data collection, is expected to take approximately two years.

About Neuralstem China

Founded in 2010, Neuralstem China (Suzhou Sun-Now Biopharmaceutical Co. Ltd. is a wholly-owned subsidiary of Neuralstem, Inc., headquartered in Suzhou, roughly one hundred miles west of Shanghai. Neuralstem China has constructed a clinical-grade manufacturing facility), and holds the license required by the Chinese government for conducting business in China. Neuralstem's mission in China is to bring its world-leading neural stem cell technology to China to address the unmet medical needs of tens of millions of patients suffering from diseases of, and injuries to, the central nervous system (CNS).

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Neuralstem Approved To Commence Ischemic Stroke Trial In China

Public release date: 27-Sep-2012 [ | E-mail | Share ]

Contact: Jennifer Schutz newsbureau@mayo.edu 507-284-5005 Mayo Clinic

ROCHESTER, Minn. -- Mayo Clinic researchers have found a way to detect and eliminate potentially troublemaking stem cells to make stem cell therapy safer. Induced Pluripotent Stem cells, also known as iPS cells, are bioengineered from adult tissues to have properties of embryonic stem cells, which have the unlimited capacity to differentiate and grow into any desired types of cells, such as skin, brain, lung and heart cells. However, during the differentiation process, some residual pluripotent or embryonic-like cells may remain and cause them to grow into tumors.

"Pluripotent stem cells show great promise in the field of regenerative medicine; however, the risk of uncontrolled cell growth will continue to prevent their use as a therapeutic treatment," says Timothy Nelson, Ph.D., M.D., lead author on the study, which appears in the October issue of STEM CELLS Translational Medicine.

Using mouse models, Mayo scientists overcame this drawback by pretreated stem cells with a chemotherapeutic agent that selectively damages the DNA of the stem cells, efficiently killing the tumor-forming cells. The contaminated cells died off, and the chemotherapy didn't affect the healthy cells, Dr. Nelson says.

"The goal of creating new therapies is twofold: to improve disease outcome with stem cell-based regenerative medicine while also ensuring safety. This research outlines a strategy to make stem cell therapies safer for our patients while preserving their therapeutic efficacy, thereby removing a barrier to translation of these treatments to the clinic," says co-author Alyson Smith, Ph.D.

Stem cell therapies continue to be refined and improved. Researchers are finding that stem cells may be more versatile than originally thought, which means they may be able to treat a wider variety of diseases, injuries and congenital anomalies. Stem cell therapy is an emerging regenerative strategy being studied at Mayo Clinic.

"By harnessing the potential of regenerative medicine, we'll be able to provide more definitive solutions to patients," says Andre Terzic, M.D., Ph.D., co-author and director of Mayo Clinic's Center for Regenerative Medicine.

###

Other members of the Mayo research team included Clifford Folmes, Ph.D., Katherine Hartjes, Natalie Nelson and Saji Oommen, Ph.D. The research was supported by the Todd and Karen Wanek Family Program for Hypoplastic Left Heart Syndrome, National Institutes of Health New Innovator Award OD007015-01, and a Mayo Clinic Center for Regenerative Medicine accelerated research grant.

Read this article:
Mayo Clinic finds way to weed out problem stem cells, making therapy safer

Featured Article Academic Journal Main Category: Stem Cell Research Also Included In: Biology / Biochemistry Article Date: 28 Sep 2012 - 1:00 PDT

Current ratings for: Purging Stem Cells To Make Therapy Safer

The study appears in a 27 September issue of the journal Stem Cells Translational Medicine.

iPS cells have properties similar to embryonic stem cells, which are "master cells" with an unlimited capacity to differentiate into any type of tissue in the body, such as brain, lung, skin, heart, and liver. Thus their potential in regenerative medicine, where damaged or diseased tissue can be repaired or replaced by growing new tissue, is huge, as senior author Timothy Nelson explains in a press release:

"Pluripotent stem cells show great promise in the field of regenerative medicine; however, the risk of uncontrolled cell growth will continue to prevent their use as a therapeutic treatment."

Nelson is Assistant Professor of Medicine and Pharmacology and works in the General Internal Medicine department and the Transplant Center at the Mayo.

The idea of using iPS cells is for doctors to be able to take some adult tissue, for example skin cells, from the patient who needs the treatment, and then turn the cells from that tissue into iPS cells.

Then, those iPS cells are coaxed to turn into the target type of cell, for instance lung cells. As a result of the coaxing the iPS cells turn into (differentiate) the target tissue type.

But current ways of doing this leaves some iPS cells undifferentiated, so they get transplanted into the patient along with the differentiated cells, leaving the risk that they will differentiate on their own in an uncontrolled way and form tumors.

For their study, Nelson and colleagues used lab mice to show that pretreating iPS cells with a chemotherapy drug, selectively damages the DNA of the stem cells, killing them off so they cannot grow uncontrollably and form tumors. The chemotherapy kills the iPS cells by triggering cell suicide or apoptosis, which is a natural response to DNA damage.

See more here:
Purging Stem Cells To Make Therapy Safer

ScienceDaily (Sep. 25, 2012) The process researchers use to generate induced pluripotent stem cells (iPSCs) -- a special type of stem cell that can be made in the lab from any type of adult cell -- is time consuming and inefficient. To speed things up, researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) turned to kinase inhibitors. These chemical compounds block the activity of kinases, enzymes responsible for many aspects of cellular communication, survival, and growth.

As they outline in a paper published September 25 in Nature Communications, the team found several kinase inhibitors that, when added to starter cells, help generate many more iPSCs than the standard method. This new capability will likely speed up research in many fields, better enabling scientists around the world to study human disease and develop new treatments.

"Generating iPSCs depends on the regulation of communication networks within cells," explained Tariq Rana, Ph.D., program director in Sanford-Burnham's Sanford Children's Health Research Center and senior author of the study. "So, when you start manipulating which genes are turned on or off in cells to create pluripotent stem cells, you are probably activating a large number of kinases. Since many of these active kinases are likely inhibiting the conversion to iPSCs, it made sense to us that adding inhibitors might lower the barrier."

According to Tony Hunter, Ph.D., professor in the Molecular and Cell Biology Laboratory at the Salk Institute for Biological Studies and director of the Salk Institute Cancer Center, "The identification of small molecules that improve the efficiency of generating iPSCs is an important step forward in being able to use these cells therapeutically. Tariq Rana's exciting new work has uncovered a class of protein kinase inhibitors that override the normal barriers to efficient iPSC formation, and these inhibitors should prove useful in generating iPSCs from new sources for experimental and ultimately therapeutic purposes." Hunter, a kinase expert, was not involved in this study.

The promise of iPSCs

At the moment, the only treatment option available to many heart failure patients is a heart transplant. Looking for a better alternative, many researchers are coaxing stem cells into new heart muscle. In Alzheimer's disease, researchers are also interested in stem cells, using them to reproduce a person's own malfunctioning brain cells in a dish, where they can be used to test therapeutic drugs. But where do these stem cells come from? Since the advent of iPSC technology, the answer in many cases is the lab. Like their embryonic cousins, iPSCs can be used to generate just about any cell type -- heart, brain, or muscle, to name a few -- that can be used to test new therapies or potentially to replace diseased or damaged tissue.

It sounds simple enough: you start with any type of differentiated cell, such as skin cells, add four molecules that reprogram the cells' genomes, and then try to catch those that successfully revert to unspecialized iPSCs. But the process takes a long time and isn't very efficient -- you can start with thousands of skin cells and end up with just a few iPSCs.

Inhibiting kinases to make more iPSCs

Zhonghan Li, a graduate student in Rana's laboratory, took on the task of finding kinase inhibitors that might speed up the iPSC-generating process. Scientists in the Conrad Prebys Center for Chemical Genomics, Sanford-Burnham's drug discovery facility, provided Li with a collection of more than 240 chemical compounds that inhibit kinases. Li painstakingly added them one-by-one to his cells and waited to see what happened. Several kinase inhibitors produced many more iPSCs than the untreated cells -- in some cases too many iPSCs for the tiny dish housing them. The most potent inhibitors targeted three kinases in particular: AurkA, P38, and IP3K.

Working with the staff in Sanford-Burnham's genomics, bioinformatics, animal modeling, and histology core facilities -- valuable resources and expertise available to all Sanford-Burnham scientists and the scientific community at large -- Rana and Li further confirmed the specificity of their findings and even nailed down the mechanism behind one inhibitor's beneficial actions.

See the original post:
Making it easier to make stem cells: Kinase inhibitors lower barrier to producing stem cells in lab

(SACRAMENTO, Calif.) - Deborah K. Lieu, a stem cell scientist in cardiovascular medicine at UC Davis Health System, has received a $1.3 million research grant from the California Institute for Regenerative Medicine (CIRM) to develop stem cells that could serve as a biological alternative to the electronic pacemakers that people now use to regulate heart rhythm.

According to Lieu, each year 350,000 cardiology patients with abnormal heart rhythms receive electronic pacemakers to maintain a normal heart beat. The devices, while effective, have several disadvantages, including limited battery life and poor response to changing heart rates, such as when a person is exercising. Lieu, who is working with colleague Nipavan Chiamvimonvat, the Roger Tatarian Endowed Professor of Cardiovascular Medicine at UC Davis, plans to examine ways to improve the generation of pacemaking cells using human-induced pluripotent stem cells (hiPSCs), potentially creating what she calls a "biopacemaker."

"There are more than 3 million patients around the country who are dependent on electronic pacemakers," said Lieu. "Each one costs about $58,000 to implant and requires follow-up surgery about every 5 to 10 years to change batteries. Creating a biopacemaker from stem cells would avoid the burden of battery replacement and provide the physiological benefit of enabling a person's heart to naturally adapt to a rising heart rate during activities such as exercise."

Lieu's grant was among more than two dozen projects that received support from state stem cell agency's governing board last week as part of CIRM's Basic Biology awards program. The funding focuses on basic research projects that can provide a better understanding about the fundamental mechanisms of stem cell biology and move researchers closer to knowing how best to use stem cells to help patients.

To create the pacemaking cells, Lieu and her colleagues plan to manipulate an ion channel (the SK channels in cardiac myocytes) to alter the calcium signaling mechanisms during hiPSC differentiation. Stem cell scientists create hiPSCs - typically from an adult cell such as a skin cell - by inducing a "forced" expression of specific genes. Once reprogrammed, the cells take on a variety of capabilities (becoming pluripotent) and offer a range of stem cell treatment possibilities.

Development of a biopacemaker could also benefit the one-in-20,000 infants and premature babies suffering from congenital heart-rhythm dysfunction who currently are not suitable candidates for electronic pacemakers. Infants are physically too small for the device. A biological pacemaker could fit with their small stature and then grow as the infant grows.

Collaborating with Lieu and Chiamvimonvat on the research project will be Jan Nolta, director of the UC Davis Institute for Regenerative Cures; Donald Bers, chair of the UC Davis Department of Pharmacology; and James Chan, assistant professor in the Department of Pathology and affiliated with the NSF Center for Biophotonics Science and Technology at UC Davis.

UC Davis is playing a leading role in regenerative medicine, with nearly 150 scientists working on a variety of stem cell-related research projects at campus locations in both Davis and Sacramento. The UC Davis Institute for Regenerative Cures, a facility supported by the California Institute for Regenerative Medicine (CIRM), opened in 2010 on the Sacramento campus. This $62 million facility is the university's hub for stem cell science. It includes Northern California's largest academic Good Manufacturing Practice laboratory, with state-of-the-art equipment and manufacturing rooms for cellular and gene therapies. UC Davis also has a Translational Human Embryonic Stem Cell Shared Research Facility in Davis and a collaborative partnership with the Institute for Pediatric Regenerative Medicine at Shriners Hospital for Children Northern California. All of the programs and facilities complement the university's Clinical and Translational Science Center, and focus on turning stem cells into cures. For more information, visit http://www.ucdmc.ucdavis.edu/stemcellresearch.

More:
Pacemaker from Stem Cells Receives Research Funding

Public release date: 25-Sep-2012 [ | E-mail | Share ]

Contact: Heather Buschman hbuschman@sanfordburnham.org 858-795-5343 Sanford-Burnham Medical Research Institute

LA JOLLA, Calif., September 25, 2012 The process researchers use to generate induced pluripotent stem cells (iPSCs)a special type of stem cell that can be made in the lab from any type of adult cellis time consuming and inefficient. To speed things up, researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) turned to kinase inhibitors. These chemical compounds block the activity of kinases, enzymes responsible for many aspects of cellular communication, survival, and growth. As they outline in a paper published September 25 in Nature Communications, the team found several kinase inhibitors that, when added to starter cells, help generate many more iPSCs than the standard method. This new capability will likely speed up research in many fields, better enabling scientists around the world to study human disease and develop new treatments.

"Generating iPSCs depends on the regulation of communication networks within cells," explained Tariq Rana, Ph.D., program director in Sanford-Burnham's Sanford Children's Health Research Center and senior author of the study. "So, when you start manipulating which genes are turned on or off in cells to create pluripotent stem cells, you are probably activating a large number of kinases. Since many of these active kinases are likely inhibiting the conversion to iPSCs, it made sense to us that adding inhibitors might lower the barrier."

According to Tony Hunter, Ph.D., professor in the Molecular and Cell Biology Laboratory at the Salk Institute for Biological Studies and director of the Salk Institute Cancer Center, "The identification of small molecules that improve the efficiency of generating iPSCs is an important step forward in being able to use these cells therapeutically. Tariq Rana's exciting new work has uncovered a class of protein kinase inhibitors that override the normal barriers to efficient iPSC formation, and these inhibitors should prove useful in generating iPSCs from new sources for experimental and ultimately therapeutic purposes." Hunter, a kinase expert, was not involved in this study.

The promise of iPSCs

At the moment, the only treatment option available to many heart failure patients is a heart transplant. Looking for a better alternative, many researchers are coaxing stem cells into new heart muscle. In Alzheimer's disease, researchers are also interested in stem cells, using them to reproduce a person's own malfunctioning brain cells in a dish, where they can be used to test therapeutic drugs. But where do these stem cells come from? Since the advent of iPSC technology, the answer in many cases is the lab. Like their embryonic cousins, iPSCs can be used to generate just about any cell typeheart, brain, or muscle, to name a fewthat can be used to test new therapies or potentially to replace diseased or damaged tissue.

It sounds simple enough: you start with any type of differentiated cell, such as skin cells, add four molecules that reprogram the cells' genomes, and then try to catch those that successfully revert to unspecialized iPSCs. But the process takes a long time and isn't very efficientyou can start with thousands of skin cells and end up with just a few iPSCs.

Inhibiting kinases to make more iPSCs

Zhonghan Li, a graduate student in Rana's laboratory, took on the task of finding kinase inhibitors that might speed up the iPSC-generating process. Scientists in the Conrad Prebys Center for Chemical Genomics, Sanford-Burnham's drug discovery facility, provided Li with a collection of more than 240 chemical compounds that inhibit kinases. Li painstakingly added them one-by-one to his cells and waited to see what happened. Several kinase inhibitors produced many more iPSCs than the untreated cellsin some cases too many iPSCs for the tiny dish housing them. The most potent inhibitors targeted three kinases in particular: AurkA, P38, and IP3K.

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Making it easier to make stem cells

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