Month: May 2015

Stem cell stories that caught our eye: Spinal cord injury, secret of creating complex tissue, mini brains in a dish and funding

/ Don Gibbons / 1 Comment

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Monkey trial provides some hope for spinal cord injury. Stem cell treatments have made many mice and rats walk again after spinal cord injury, but moving from those rodents to human has been a slow process. Their immune systems and nervous systems are very different from ours. So, it was good to read this week that a team at Japan’s Keio University reported success in monkeys with systems much more like ours.

The experiment was “controlled.” They compared treated and non-treated animals and saw a significant difference in mobility between the two groups. Bloomberg picked up the release from the journal that published the work Stem Cells Translational Medicine, which quoted the study author Hideyuki Okano:

“An animal in the control group, for example, could not raise her hands up to head height at 12 weeks after injury when motor function almost plateaus. On the other hand, at the same point in time a transplanted animal was able to jump successfully and run so fast it was difficult for us to catch her. She could also grip a pen at 3 cm. above head-height.”

But the work requires some caveats. They treated all animals at exactly 14-days post injury, a window considered optimal for having initial inflammation subside and scar tissue not yet formed. Also, the researchers inflicted bruises not more severe damage to the spinal cord. Most patients with spinal cord injury are chronic, long past the 14-day window, and have damage to their spinal cords more severe than these animals.

The researchers started with embryonic stem cells and matured them into nerve progenitor cells, which they injected into the monkeys. While this process can yield plentiful cells for therapy the researchers acknowledged that much more research is needed before they can help the vast majority of spinal cord injuries with more severe and older injuries. CIRM funds a clinical trial using cells derived from embryonic stem cells to treat more complex spinal injuries, but it is just getting underway.

Clues to creating complex tissues. These days getting stem cells to form a single type of tissue, nerve or skin for example, is almost routine, with the remaining hurdle being purity. But getting stem cells to form complex tissues with multiple types of cells, while done a few times, still gets folks attention. For the most part, this is because we don’t know the cell-to-cell interactions required to form complex tissues. A CIRM-funded team at the University of California, San Diego, thinks they have part of the answer.

They studied something called the neurovascular unit, made up of blood vessels, smooth muscle and nerves that regulate heart rate, blood flow and breathing, among other basic functions. Using a lab model they showed how the different cell types come together to form the vital regulatory tissue. San Diego Newscape posted a piece on the work, quoting the study’s senor author David Cheresh:

“This new model allows us to follow the fate of distinct cell types during development, as they work cooperatively, in a way that we can’t in intact embryos, individual cell lines or mouse models. And if we’re ever going to use stem cells to develop new organ systems, we need to know how different cell types come together to form complex and functional structures such as the neurovascular unit.”

And a brainy example.   Prior research has created small brain “organoids” that started with stem cells and self assembled in a lab dish to create layers of nerves and support cells, but the cells did not interact much like normal brain tissue. Now, a team at Stanford has developed “cortex-like spheroids” with different types of cells that talk to each other.

Nerves and supporting cells form layers and organize like in the developing brain

Nerves and supporting cells form layers and organize like in the developing brain

In the new cortex spheres the nerves are healthier with a better network of the natural supporting cells called glial cells. The cells form layers that interact with each other like in our brains as we are developing.

A program at the National Institutes of Health (NIH) focusing on using stem cells to create models of disease in the lab funded the work. Thomas Insel, Director of the NIH’s National Institute of Mental Health described the importance of the current work in a press release from the institute picked up by HealthCanal:

 

“There’s been amazing progress in this field over the past few years. The cortex spheroids grow to a state in which they express functional connectivity, allowing for modeling and understanding of mental illnesses. They do not even begin to approach the complexity of a whole human brain. But that is not exactly what we need to study disorders of brain circuitry.“

The release starts with a fun lede imagining the day when a patient tormented by mental illness could have a model of their disease grown in a dish and researchers could genetically engineer better brain circuits for the patient. Certainly not just around the corner, but not far fetched.

States economic gain from funding research. The very niched web cite Governing posted a piece that appears to be largely from a conference in Washington D.C. hosted by the Greater Phoenix Economic Council. It quotes several experts speaking about the opportunity for states to gain economic advantage by funding research.

The piece notes some well documented examples of federal government spending on research spawning industries—think Silicon Valley. Then it talks about some more recent state examples including the California initiative that created CIRM.

One speaker, Mark Muro of the Brookings Institute said that we are in a new era now and states may not be able to fund research through their general tax revenue. He said:

“It may be the state becoming part of a consortium or working with Fortune 500 companies, or going to voters with a general obligation bond vote. I think we’re heading for a new complexity.”

Since CIRM was created through a vote for bonds, guess we have to agree.

New Stem Cell Book Chronicles California’s Fight Against Incurable Disease

/ Todd Dubnicoff / 2 Comments

In 2098, the world will mark 100 years since the first isolation of human embryonic stem cells. The historians of that time undoubtedly will praise the countless stem cell researchers who fought incurable, chronic disease and won – saving lives and transforming medicine in the process.

StemCellBattlesCoverBut they’ll also applaud the efforts of non-scientists like Don Reed, a tenacious advocate for stem cell research and for people living with chronic disease and disability. No doubt those future historians will heavily reference Don’s soon to be released book, STEM CELL BATTLES: Proposition 71 and Beyond: How Ordinary People Can Fight Back Against the Crushing Burden of Chronic Disease. Through first-hand accounts, he chronicles the early battles to get human stem cell research off the ground in California, the progress that’s been made so far and the promise for future therapies.

It’s no coincidence that Stem Cell Battles will hit the bookshelves on October 14th, World Stem Cell Awareness Day. In anticipation of the book’s release, Don will blog every Wednesday from now until then.

Each week, the blog series will focus on one incurable disease or injury and describe the CIRM-funded project teams aiming to develop stem cell-based treatments. Yesterday’s blog is devoted to Amyotrophic Lateral Sclerosis (ALS) commonly known as Lou Gehrig’s disease.

We enjoy his easy to understand writing style peppered with concrete statistics that puts the disease’s impact in perspective. We also appreciate the fact Don speaks highly of CIRM’s accomplishments. But please know that we didn’t put him up to it. We are not paying Don or doing anything other than providing him with whatever information he asked for, the same way we work with any journalist, writer or member of the public.

Follow Don’s disease-a-week series at his blog, Stem Cell Battles.

Faster, better, more efficient. Challenging? That too. An update on CIRM 2.0.

/ Kevin McCormack / Leave a comment

Changing direction is never easy. The greater the change the greater the likelihood you’ll have to make adjustments and do some fine-tuning along the way to make sure you get it right.

On January 1st of this year we made a big change, launching CIRM 2.0. Our President and CEO Dr. C. Randal Mills called it “a radical overhaul of the way the Agency does business.” This new approach puts the emphasis on patients, partnerships and speed and cuts down the time from application to funding of clinical-stage projects from around two years to just 120 days.

You can read more about 2.0 here.

So, several months into the program how are we doing?

Clinical stage of CIRM 2.0 has three programs

Clinical stage of CIRM 2.0 has three programs

Well, since January 1st we have had three application tracks under 2.0 that reflect our goal of accelerating therapies to patients with unmet medical needs. These focus on late stage work to either get a promising therapy into a clinical trial, to carry out a clinical trial, or to help a promising project move even faster.

Under those three programs we have had 12 applications for funding, for a total request of $111 million. With application deadlines the last business day of each month two of those were in January, two in February, three more in March and five in April.

As Dr. Mills told our governing Board when they met last week, that number is more than we were expecting:

 “When we started the program we calculated there’d be around one or two applications a month, not five. I don’t think having five applications a month is sustainable, but that’s probably just the backlog, the pent up demand for funding, working its way through the system. For now we can cope with that volume.”

Interestingly eight of those applications were for funding for clinical trials:

  • Two for Phase 1
  • One for Phase 2
  • Five for Phase 3

Last week our Board approved one of those Phase 3 trials (the last big hurdle to clear before the Food and Drug Administration will consider approving it for wider use), investing almost $18 million in NeoStem’s therapy for one of the deadliest forms of skin cancer, metastatic melanoma.

This is the first time we have ever funded a Phase 3 trial. So, quite a milestone for us. But it may well not be the last one. The Board also approved a project to conduct the late preclinical work needed to apply to conduct a trial in retinitis pigmentosa.

Dr. Mills said there are two clear patterns so far:

“We are getting a more mature portfolio of clinical stage programs for adjudication. We are also starting to see requests for accelerating activities, where we have made previous awards to researchers who now have identified new ways to accelerate that work and they are turning to us for help in doing that.”

Of the 12 applications received we have screened all of them within the 7-day target window to make sure they meet funding criteria. Some have been ruled out for not being within the scope of the award program. The accepted applications have all had budget reviews and been sent on for expert analysis within the slated time frames.

We had a couple of hiccups with our first review but that resulted from on-line technology and getting everyone comfortable with the new rules we were bringing in. The second review resulted in the first two awards by our Board last week, and the third review occurred yesterday.

“The bottom line is things are moving through and things are being weeded out. In March we had two clinical stage applications and one add-on funding application but that one add-on failed in screening. So, in general CIRM 2.0 is being well utilized. There’s no question we are significantly reducing application time from application to funding, attracting later stage applications. Clearly this has not been without its challenges but the team is doing a great job of managing everything.”

And remember this is only the first part of CIRM 2.0. We have two other programs, for Discovery or basic research and Translational research, that are being developed and we plan on rolling those out later this summer.

Stay tuned for more details on those programs.

Old brains in mice given a trait of young brains with embryonic nerve transplant

/ Don Gibbons / Leave a comment

As we age our brains become less adept at making new nerve connections or repairing broken ones. A CIRM-funded team at the University of California, Irvine, restored this youthful ability, called nerve plasticity, to adult mice by transplanting embryonic nerve cells.

old to young

Specifically, they worked with mice that had a form of blurred vision known as amblyopia and the nerve cells they transplanted were ones that produce the nerve signal GABA. That amino acid helps regulate many aspects of brain function, including vision. The transplanted nerve cells allowed the brain to rewire itself and make connections that were missing and causing the poor vision. Several weeks later, the mice started to see normally.

The researchers transplanted the new cells directly into the visual cortex where the new nerve connections were needed. The mice had developed amblyopia, like humans, because the proper nerve connections failed to develop during a critical period when they were young. At the point in time that the transplanted embryonic cells would be going through that same critical period is when the researchers saw the improvement in vision for the adult mice. In a press release picked up at MedMerits.com the leader of the team, Sonil Gandhi explained what they saw:

“These experiments make clear that developmental mechanisms located within these GABA cells control the timing of the critical period.”

Gandhi added that the work should open up the possibility of trying to use GABA cell transplants to retrain the brain after injury or to repair congenital defects.

The news site NewsMax wrote an article on the research adding a bit more analysis.

Stem cell stories that caught our eye: sickle cell patient data, vaccine link to leukemia protection, faster cell analysis

/ Don Gibbons / 1 Comment

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Good news from sickle cell clinical trial. It is always satisfying to report positive results from human clinical trials using stem cells even when we don’t fund the work. Bluebird Bio released the first data on a patient treated for sickle cell anemia using the same procedure the company had earlier used to get good outcomes for two patients with beta thalassemia.

Both diseases result from defects—though different defects—in the gene for hemoglobin, the protein our red blood cells use to carry needed oxygen. So, in both cases they use a modified, deactivated virus to carry a correct version of the gene into patients’ own blood-forming stem cells in the lab. They then re-infused those cells into the patients to provide a ready supply of cells able to make the needed protein.

In the sickle cell patient, after the transplant a third of his red cells were making the right protein and that was enough to wean him off blood transfusions that had been keeping him alive and prevented any further hospitalizations due to the disease. The company also announced that the two previously reported patients treated for beta thalassemia had continued to improve. Reuters ran a story on the new data.

CIRM funds a similar project about to begin treating patients for sickle cell disease (link to video), also using a viral vector but a somewhat different one, so it is reassuring to see viral gene carriers working without side effects.

Another reason to vaccinate, prevent leukemia. While it has been known for some time that infant vaccination seems to have driven down the rate of childhood leukemia, no one has known why. A CIRM-funded team at the University of California, San Francisco, thinks they have figured it out. Viral infections trigger inflammation and the production of enzymes in cells that cause genetic mutations that lead to the cancer.

They worked with Haemophilus influenza Type b (Hib) vaccine but suggest a similar mechanism probably applies to other viral infections, and correspondingly, protection from other vaccines. The senior author on the paper, Marcus Muschen, explained the process in a university press release posted at Press-News.org

“These experiments help explain why the incidence of leukemia has been dramatically reduced since the advent of regular vaccinations during infancy. Hib and other childhood infections can cause recurrent and vehement immune responses, which we have found could lead to leukemia, but infants that have received vaccines are largely protected and acquire long-term immunity through very mild immune reactions.”

Barcoding individual cells. Our skin cells all pretty much look the same, but in the palm of your hand there are actually several different types of cells, even a tiny scratch of the fingernail. As scientist work to better understand how cells function, and in particular how stem cells mature, they increasingly need to know precisely what genes are turned on in individual cells.

Both techniques use tiny channels to isolate individual cells and introduce beads with "bar codes."

Both techniques use tiny channels to isolate individual cells and introduce beads with “bar codes.”

Until recently, all this type of analysis blended up a bunch of cells and asked what is in the collective soup. And this did not get the fine-tuned answers today’s scientists are seeking. Numerous teams over the past couple years have reported on tools to get down to single-cell gene analysis. Now, two teams at Harvard have independently developed ways to make this easier. They both use a type of DNA barcode on tiny beads that gets incorporated into individual cells before analysis.

Allan Klein, part of one team based at the Harvard Medical School’s main campus, described why the work is needed in a detailed narrative story released by the school:

“Does a population of cells that we initially think is uniform actually have some substructure. What is the nature of an early developing stem cell? . . . How is [a cell’s] fate determined? “

Even Macosko who worked with the other team centered at the Broad Institute of Harvard and MIT, noted the considerable increase in ease and decrease in cost with the new methods compared to some of the early methods of single cell gene analysis:

“If you’re a biologist with an interesting question in mind, this approach could shine a light on the problem without bankrupting you. It finally makes gene expression profiling on a cell-by-cell level tractable and accessible. I think it’s something biologists in a lot of fields will want to use.”

The narrative provides a good example of what we called the “bump rate” when I was at Harvard Med. Good science often moves forward when scientists bump into each other, and with Harvard Medical faculty scattered at 17 affiliated hospitals and research institutes scattered across Boston and Cambridge we were always looking for ways to increase the bump rate with conferences and cross department events. Macosko and Klein found out they were both working on similar systems at a conference.

Two for 2.0 and Two for us

/ Kevin McCormack / Leave a comment

It began as an ambitious idea; yesterday it became a reality when the CIRM Board approved two projects under CIRM 2.0, one of them a Phase 3 clinical trial for a deadly form of skin cancer.

Just to recap, CIRM 2.0 was introduced by Dr. C. Randal Mills when he took over as President and CEO of the stem cell agency last year. The idea is to speed up the way we work, to get money to the most promising therapies and the best science as quickly as possible. It puts added emphasis on speed, patients and partnerships.

Yesterday our Board approved the first two projects to come before them under this new way of working. One was for almost $18 million for NeoStem, which is planning a Phase 3 clinical trial for metastatic melanoma, a disease that last year alone claimed more than 10,000 lives in the U.S.

This will be the first Phase 3 trial we have funded so clearly it’s quite a milestone for us and for NeoStem. If it proves effective in this trial it could well be approved by the Food and Drug Administration (FDA) for use in melanoma patients. The therapy itself is unique in that it uses the patient’s own tumor cells to create a personalized therapy, one that is designed to engage the patient’s immune system and destroy the cancer.

The Board also approved almost $5 million for Cedars-Sinai in Los Angeles to do the late-stage research needed to apply to the FDA for approval for a clinical trial to treat retinitis pigmentosa (RP). RP is a nasty, degenerative condition that slowly destroys a patient’s vision. There is no cure and no effective therapy.

We are currently funding another clinical trial in this area. The two projects use different types of cells and propose different methods of reducing RP’s devastation. CIRM has a record of trying multiple routes to achieve success when dealing with unmet medical needs.

As Dr. Mills said in a news release, both the therapies approved for funding yesterday support our mission:

“CIRM 2.0 is designed to accelerate the development of treatments for people with unmet medical needs, and these two projects clearly fit that description. With the Board’s approval today we will now get this work up and running within the next 45 days. But that’s just the start. We are not just providing financial support, we are also partnering with these groups to provide expertise, guidance and other kinds of support that these teams need to help them be successful. That’s the promise of CIRM 2.0. Faster funding, better programs and a more comprehensive approach to supporting their progress.”

CIRM Chair Jonathan Thomas swearing in new Board members Adriana Padilla and Bob Price

CIRM Chair Jonathan Thomas swearing in new Board members Adriana Padilla and Bob Price

Two seemed to be the number of the day yesterday with the Board welcoming two new members.

Dr. Adriana Padilla is the new Patient Advocate Board member for type 2 Diabetes. She’s a family physician, a member of the University of California, San Francisco-Fresno medical faculty, and an award-winning researcher with expertise in diabetes and its impact on Latino families and the health system in California’s Central Valley. She is also active in the National Hispanic Medical Association (NHMA) and is also a member of the American Diabetes Association.

Dr. Padilla said she hopes her presence will help increase awareness among Latinos of the importance of the work the agency is doing:

“When I was asked about being on the Board I did some research to find out more and it was really touching to learn about some of the exciting work that has been done by the agency and the possibilities that can be done for patients, including those I serve, members of the Latino community.”

Dr. Bob Price is the Associate Vice Chancellor for Research and a Professor of Political Science at U.C. Berkeley. His academic and teaching interests include comparative politics, with a particular interest in the politics of South Africa. This is Dr. Price’s second time on the Board.  He previously served as the alternate to UC Berkeley Chancellor Robert Birgeneau.

Although he has only been off the Board for a little more than a year Dr. Price said he is aware of the big changes that have taken place in that time and is looking forward to being a part of the new CIRM 2.0.

Stem cells, Darth Vader and the high cost of hope and hype

/ Kevin McCormack / Leave a comment
Darth Vader: Photo by Stefano Buttafoco

Darth Vader: Photo by Stefano Buttafoco

It’s not very often that you get stories about stem cells that mention Darth Vader, Obi Wan Kenobi, the Pittsburgh Steelers and a Beverly Hills plastic surgeon, but those references all popped up in a recent flurry of articles that are shining – yet again – the light on many of the unproven, unregulated uses of stem cells to treat everything from arthritis to Parkinson’s disease.

Let’s start with an article by Associated Press (AP) writer Will Graves who digs into the use of stem cells in sports.  Graves does a good job of highlighting all the reasons why an athlete would try a stem cell therapy quoting Dr. Jim Bradley, a team physician with the Steelers:

“They want the cutting edge, anything that is cutting edge that can get their guys a couple more years in the league. If I was an agent, I’d want the same thing.”

But Graves also does a fine job of pointing out that these therapies are unproven, and that in many cases athletes go overseas to get them because those clinics do not have to meet the same strict regulations as clinics here in the US.

“Traveling to a place like the Caymans, that’s like saying ‘I’m going to Mexico to have an appendectomy to save $80,'” said Dr. Matthew Matava, head physician for the St. Louis Rams and the NHL’s St. Louis Blues. “It looks like it’s not very smart or you’re grasping at straws.”

He also quotes Dr. Freddie Fu, head physician for the University of Pittsburgh athletics program, saying there is far too much uncertainty to take risks. Fu says in many cases the people delivering the therapies don’t even know where these stem cells might go, or what they might do:

“You can have one cell be Obi Wan Kenobi, the other is Darth Vader. You’re not sure which way it’s going to go.”

Matthew Perrone starts his piece in the Huffington Post, with a paragraph that is both gripping and disgusting:

“The liquid is dark red, a mixture of fat and blood, and Dr. Mark Berman pumps it out of the patient’s backside. He treats it with a chemical, runs it through a processor — and injects it into the woman’s aching knees and elbows.”

Berman, the co-founder of the largest chain of stem cell clinics in the US, admits he doesn’t know what’s in the mixture he is injecting into patients. But he says it can help treat more than 30 different diseases and conditions from Lou Gehrig’s disease to lupus and even erectile dysfunction.

Perrone’s piece is a long, detailed and thoughtful look at the finances that drive this business and how many stem cell clinics charge as much as $9,000 for unproven therapies. He quotes UC Davis stem cell researcher – and CIRM grantee – Dr. Paul Knoepfler:

“It’s sort of this 21st century cutting-edge technology. But the way it’s being implemented at these clinics and how it’s regulated is more like the 19th century. It’s a Wild West.”

But the price tag at those US-based clinics is tiny compared to how much some people are paying at overseas facilities. Los Angeles Times reporter Alan Zarembo focuses on the case of William Rader and his company Stem Cell of America.

Rader, a psychiatrist, had his medical license revoked by the Medical Board of California citing negligence, false or misleading advertising and professional misconduct. The Board said: “His dishonesty permeates every aspect of his business and practices.”

Yet Rader continues to charge up to $30,000 for stem cell procedures at the clinic he runs in Mexico. He uses the same procedure for different conditions, offers no scientific evidence it works but claims he’s helped many people and even cured a patient of HIV/AIDS.

For patients battling life-threatening diseases and disorders it is easy to see why they would be willing to take a chance on a therapy, any therapy, that might save their life.

And that’s where the danger in all this lies. What might be seen by an athlete as something worth trying to see if it might help extend their career a year or two, for people at the other end of life this may be their last chance, and that vulnerability means they’ll pay whatever they have to, for something that may be of no benefit whatsoever.

Telling an athlete this might help them play longer is one thing. Playing on a patient’s life or death fears is entirely another.

For more information on how you can make an informed decision about whether a stem cell therapy is right for you, particularly one offered overseas, go to our page on stem cell tourism.

Seth and Lauren Rogen Aim to Finish Alzheimer’s Film and End Lost Memories

/ Todd Dubnicoff / 1 Comment

When it comes right down to it, the closeness and love we feel for friends and family is based on our memories of shared experiences. But for Ken Dodson, those memories are evaporating:

It didn’t seem to progress as fast ‘til this year. This year I’ve noticed a lot more. I mean [my doctor] has already told me that it will be at the point where I don’t recognize any of my kids. That’s the hardest. There are some things you should never forget. I know one day I might.

Only 35 years old, Ken is stricken with early-onset Alzheimer’s. His tragic story is featured in, “This is Alzheimer’s”, a documentary being produced by film actor/writer/producer couple Seth Rogen and Lauren Miller Rogen. To help raise the funds needed to complete the project, the Rogens launched an online donation campaign, which ends tomorrow. You can view a clip of the documentary on their campaign page and below:

This film project is just one activity of the Rogens’ Hilarity for Charity (HFC) movement, which aims to raise awareness about Alzheimer’s among young adults and to fund research that could one day end this cruel disease. As mentioned on the HFC website, their efforts have been a hit so far:

For three years, our successful Los Angeles HFC Variety Show and our college program HFC U have entertained young, hip professionals through music and comedy while creating the next generation of Alzheimer’s advocates – not to mention raising over $2.5 million!

The Rogens’ innovative and inspiring charity work for Alzheimer’s hits close to home for a couple of reasons. For starters, our agency has awarded over $52 million to stem cell related Alzheimer’s research which aims to better understand the disease and to work towards bringing stem cell-based treatments to clinical trials. And Lauren Miller Rogen is not only a co-founder of Hilarity for Charity but also serves as the Alzheimer’s patient advocate on the CIRM governing Board. Alzheimer’s has personally affected Lauren’s family: Lauren lost her grandfather and grandmother to the disease and, like Ken Dodson, her mother Adele was diagnosed with early-onset Alzheimer’s at just 55 years of age. Before she reached 60, Adele couldn’t write, speak, or recognize her family.

When it comes to developing therapies for unmet medical needs, it’s crucial to approach diseases from many angles in order to identify the best approaches more efficiently. The same holds true for raising awareness and funding research. That’s why the Rogen’s documentary is an important piece to the puzzle of ending Alzheimer’s and lost memories.

Taking a step back, to move forward

/ Kevin McCormack / Leave a comment

Progress doesn’t always come in straight lines. Particularly when you are a pioneer in a whole new field of medicine like stem cells where virtually everything you do is being done for the first time, and the therapies you are developing are going to be tested in people for the first time. That’s why everything you do has to be done with extra caution to make sure the best interests of the patients come first. Sometimes that means not rushing ahead, but pausing, while you decide what is the best approach.

SangamoThat’s what Sangamo have done in announcing they are delaying the start of their clinical trial in beta thalassemia – a trial we are funding.

They are taking what amounts to a “time-out” so that they can make a small change in direction, one they – and we – hope will ultimately prove most effective for patients.

Βeta thalassemia is a genetic disease that results in patients producing red blood cells with poorly functioning hemoglobin, the protein that carries oxygen to all our tissues. If not properly managed the condition can be fatal.

The approach Sangamo are taking to cure the problem involves using zinc finger nuclease (ZFN), a kind of molecular scissors, to genetically edit the patient’s own stem cells, correcting the problem and enabling them to produce healthy hemoglobin and healthy red blood cells.

But as they geared up for the clinical trial, one that was approved by the Food and Drug Administration (FDA), they did some preclinical testing and saw that an approach they were using on a similar disease – sickle cell disease (SCD) – appeared to be more efficient and effective at correcting the underlying genetic problem. Both used ZFN to edit the defective gene, but they both had slightly different targets on those genes. The one targeting SCD seemed to have some key advantages, so they have decided to switch to this approach for both conditions.

In a news release Edward Lanphier, Sangamo’s President and CEO, says it wasn’t an easy decision to make, but it is the right decision:

“While our joint decision will result in a delay in the initiation of the beta-thalassemia Phase 1 clinical trial, we believe that the efficiency of the consolidated development path and potential benefit to patients clearly support this decision.”

The next step is for Sangamo to go back to the FDA and file a new Investigational New Drug or IND application for this new approach to beta-thalassemia. They’re hopeful they’ll be able to get that approval, and move ahead with their clinical trial next year.

The good news is that thanks to our new way of funding under CIRM 2.0, Sangamo will have the opportunity to seek CIRM’s support for its work through both our preclinical program, as they make their changes, and then our clinical program if and when they get FDA approval to move ahead. This uninterrupted support is what CIRM 2.0 was set up to achieve, to move promising projects like this to patients as quickly as possible.

For the team at Sangamo it’s obviously disappointing to have to stop and change direction. It’s also disappointing for the patients hoping this would lead to a more effective therapy, even a cure.

But this is not a set back. Rather, it’s a step back. One that allows Sangamo to choose what they believe is a better option, one that will ultimately be much better for patients.

Stem cell stories that caught our eye: reversing aging, mature hearts, arthritic knees and tiny organs

/ Don Gibbons / Leave a comment

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Young brain cells (top) show little of the molecule that impairs stem cell function (green) that is abundant in old cells (bottom).

Young brain cells (top) show little of the molecule that impairs stem cell function (green) that is abundant in old cells (bottom).

Making stem cells feels young again. Stem cells are supposed to rejuvenate our tissues, whether brain or muscle, and keep them functioning at their peak. But the aging process seems to poison the environment where stem cells reside and prevent them from getting the job done.

A CIRM-funded team at the University of California, Berkeley, has found a drug that can reverse the effect of aging and make the stem cells function better and in turn make tissues behave like younger versions of brain or muscle. Their previous work had shown that old tissues had much more of one growth factor, TGF-beta1, than young tissue. When the team, led by David Schaffer and Irina Conboy, blocked the activity of that growth factor with a cancer drug already in clinical trials they saw rejuvenated youthful tissue—in mice.

HealthCanal picked up the university’s press release, in which Schaffer described the broad effect of the treatment:

“We established that you can use a single small molecule to rescue essential function in not only aged brain tissue but aged muscle. That is good news, because if every tissue had a different molecular mechanism for aging, we wouldn’t be able to have a single intervention that rescues the function of multiple tissues.”

The team, however, noted that multiple molecular signals are in play in the aging stem cell’s environment and optimum intervention may require using more than one drug and getting the dosages just right. Conboy said that the task was to “recalibrate the environment to be youth-like.”

Maturing of the heart. Scientists can turn embryonic stem cells into most forms of adult tissue, but often those tissues don’t function like fully mature forms of the organ they are supposed to be. Now a consortium of researchers has identified a molecular switch that seems to be able to take stem cells and get them to form fully mature heart muscle.

In an interview with Genetic Engineering & Biotechnology News, senior author on the paper Hannele Ruohola-Baker of the University of Washington noted the breakthrough:

“Although we can now induce embryonic stem cells to become heart cells, getting them to mature to an adult-like state remains a significant challenge. We believe we’ve now found the master switch that drives the maturation process.”

The researchers found the molecular switch by studying many of the genetic switches called micro-RNAs in both young and old heart muscle cells. The one linked to helping stem cells mature interestingly is also involved in up-regulating metabolism and it makes sense that a supercharged metabolism would be valuable for fully functional heart muscle.

Some answers may be coming on stem cells and knees. While many clinics around the word offer to treat arthritic knees with stem cells taken from a patient’s own fat—often for large sums of money—very little data exist on the outcomes of those treatments. So, it was great to read this week that a European consortium is about to launch a large trial that should provide some quality data.

The ADIPOA-2 trial will enroll 150 patients in a randomized way so that the stem cell treatment can be compared to standard therapies, and the researchers will handle processing of the fat stem cells in a consistent way across clinics in four countries. It follows a phase 1 ADIPOA trial with 18 patients that showed promising results.

Frank Barry of the National University of Ireland Galway is coordinating the phase 2 trial and was quoted in the university’s press release picked up by HealthCanal:

“The results from ADIPOA’s first-in-man-trials were very encouraging and paved the way for another study to further test the safety and effectiveness on a wider scale. ADIPOA-2 is bringing together Europe’s leading scientific, clinical and technical expertise on this project.”

A lingering question remains about how long any benefit from the stem cell therapy will last. Some researchers have suggested that fat stem cells can only form soft cartilage like in your ear lobe and not the articular hard cartilage normally in your knee. So, it will take some years of follow-up to see if any new cartilage made by the stem cells can stand up to the beating of a good tennis match or hike up a mountain.

CIRM funds a research team at the University of Calirfornia, San Diego, that believe they have found a way to get embryonic stem cells, which are more versatile than fat stem cells, to form the hard articular cartilage.

Great hope in tiny little organs. For the past couple years one of the hottest areas of stem cell science has been growing stem cells in 3-D cultures in the lab and getting them to self organize into multi-tissue layers that mimic some function of one of our vital organs. It has been done for the eye, lung, liver, kidney and brain, but the first was the intestine, and the researcher behind the advance, Hans Clevers, dubbed them “organoids.”

The journal Nature just published a good Q&A interview with Clevers who works at the Hubrecht Institute Utrecht, the Netherlands. In it he describes how organoids will be a useful tool for drug screening and how his team is working on ways that organoids made from a patient’s own cells could be tested in the lab for sensitivity to specific cancer therapies.