Funding stem cell research targeting a rare and life-threatening disease in children


Photo courtesy Cystinosis Research Network

If you have never heard of cystinosis you should consider yourself fortunate. It’s a rare condition caused by an inherited genetic mutation. It hits early and it hits hard. Children with cystinosis are usually diagnosed before age 2 and are in end-stage kidney failure by the time they are 9. If that’s not bad enough they also experience damage to their eyes, liver, muscles, pancreas and brain.

The genetic mutation behind the condition results in an amino acid, cystine, accumulating at toxic levels in the body. There’s no cure. There is one approved treatment but it only delays progression of the disease, has some serious side effects of its own, and doesn’t prevent the need for a  kidney transplant.

Researchers at UC San Diego, led by Stephanie Cherqui, think they might have a better approach, one that could offer a single, life-long treatment for the problem. Yesterday the CIRM Board agreed and approved more than $5.2 million for Cherqui and her team to do the pre-clinical testing and work needed to get this potential treatment ready for a clinical trial.

Their goal is to take blood stem cells from people with cystinosis, genetically-modify them and return them to the patient, effectively delivering a healthy, functional gene to the body. The hope is that these genetically-modified blood stem cells will integrate with various body organs and not only replace diseased cells but also rescue them from the disease, making them healthy once again.

In a news release Randy Mills, CIRM’s President and CEO, said orphan diseases like cystinosis may not affect large numbers of people but are no less deserving of research in finding an effective therapy:

“Current treatments are expensive and limited. We want to push beyond and help find a life-long treatment, one that could prevent kidney failure and the need for kidney transplant. In this case, both the need and the science were compelling.”

The beauty of work like this is that, if successful, a one-time treatment could last a lifetime, eliminating or reducing kidney disease and the need for kidney transplantation. But it doesn’t stop there. The lessons learned through research like this might also apply to other inherited multi-organ degenerative disorders.

Stem cell stories that caught our eye: improving heart care, fixing sickle cell disease, stem cells & sugar

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.

Using “disease in a dish” model to improve heart care
Medications we take to improve our quality of life might actually be putting our lives in danger. For example, some studies have shown that high doses of pain killers like ibuprofen can increase our risk of heart problems or stroke. Now a new study has found a way of using a person’s own cells, to make sure the drugs they are given help, and don’t hinder their recovery.


Cardiac muscle cells from boy with inherited heart arrhythmia.
Image: Emory University

Researchers at Emory University in Atlanta took skin cells from a teenage boy with an inherited heart arrhythmia, and turned them into induced pluripotent stem (iPS) cells – a kind of cell that can then be turned into any other cell in the body. They then turned the iPS cells into heart muscle cells and used those cells to test different medications to see which were most effective at treating the arrhythmia, without causing any toxic or dangerous side effects.

The study was published in Disease Models & Mechanisms. In a news release co-author Peter Fischbach, said the work enables them to study the impact on a heart cell, without taking any heart cells from patients:

“We were able to recapitulate in a petri dish what we had seen in the patient. The hope is that in the future, we will be able to do that in reverse order.”

Switching a gene “off” to ease sickle cell disease pain:
Sickle cell disease (SCD) is a nasty, inherited condition that not only leaves people in debilitating pain, but also shortens their lives. Now researchers at Dana-Farber and Boston Children’s Cancer and Blood Disorders Center have found a way that could help ease that pain in some patients.

SCD is caused by a mutation in hemoglobin, which helps carry oxygen around in our blood. The mutation causes normally soft, round blood cells to become stiff and sickle-shaped. These often stick together, blocking blood flow, causing intense pain, organ damage and even strokes.

In this study, published in the Journal of Clinical Investigation, researchers took advantage of the fact that SCD is milder in people whose red blood cells have a fetal form of hemoglobin, something which for most of us tails off after we are born. They found that by “switching off” a gene called BCL11A they could restart that fetal form of hemoglobin.

They did this in mice successfully. Senior author David Williams, in a story picked up by Health Medicine Network, says they now hope to try this in people:

“BCL11A represses fetal hemoglobin, which does not lead to sickling, and also activates beta hemoglobin, which is affected by the sickle-cell mutation. So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in sickle cell disease.”

CIRM already has a similar approach in clinical trials. UCLA’s Don Kohn is using a genetic editing technique to add a novel therapeutic hemoglobin gene that blocks sickling of the red blood cells and hopefully cure the patient altogether. This fun video gives a quick summary of the clinical trial:

How a stem cell’s sugar metabolism controls its transformation potential
While CIRM makes its push to fund 50 more stem cell-based clinical trials by 2020, we also continue to fund research that helps us better understand stem cells. Case in point, this week a UCLA research team funded in part by CIRM reported that an embryonic stem cell’s sugar metabolism changes as its develops and that this difference has big implications on cell fate.



The study, published in Cell Stem Cell, compared so-called “naïve” and “primed” human embryonic stem cells (ESCs). The naïve cells represent a very early stage of embryo development and the primed cells represent a slightly later stage. All cells use the sugar, glucose, to provide energy, though the researchers discovered that the naive stem cells “ate up” glucose four times faster than the primed stem cells (A fascinating side note is they also found the exact opposite behavior in mice: naïve mouse ESCs metabolize glucose slower than primed mouse ESCs. This is a nice example of why it’s important to study human cells to understand human biology). It turns out this difference effects each cells ability to differentiate, or specialize, into a mature cell type. When the researchers added a drug that inhibits glucose metabolism to the naïve cells and stimulated them down a brain cell fate, three times more of the cells specialized into nerve cells.

Their next steps are to understand exactly how the change in glucose metabolism affects differentiation. As Heather Christofk mentioned in a university press release, these findings could ultimately help researchers who are manipulating stem cells to develop cell therapy products:

“Our study proves that if you carefully alter the sugar metabolism of pluripotent stem cells, you can affect their fate. This could be very useful for regenerative medicine.”

Multi-Talented Stem Cells: The Many Ways to Use Them in the Clinic

CIRM kicked off the 2016 International Society for Stem Cell Research (ISSCR) Conference in San Francisco with a public stem cell event yesterday that brought scientists, patients, patient advocates and members of the general public together to discuss the many ways stem cells are being used in the clinic to develop treatments for patients with unmet medical needs.

Bruce Conklin, Gladstone Institutes & UCSF

Bruce Conklin, Gladstone Institutes & UCSF

Bruce Conklin, an Investigator at the Gladstone Institutes and UCSF Professor, moderated the panel of four scientists and three patient advocates. He immediately captured the audience’s attention by showing a stunning video of human heart cells, beating in synchrony in a petri dish. Conklin explained that scientists now have the skills and technology to generate human stem cell models of cardiomyopathy (heart disease) and many other diseases in a dish.

Conklin went on to highlight four main ways that stem cells are contributing to human therapy. First is using stem cells to model diseases whose causes are still largely unknown (like with Parkinson’s disease). Second, genome editing of stem cells is a new technology that has the potential to offer cures to patients with genetic disorders like sickle cell anemia. Third, stem cells are known to secrete healing factors, and transplanting them into humans could be beneficial. Lastly, stem cells can be engineered to attack cancer cells and overcome cancer’s normal way of evading the immune system.

Before introducing the other panelists, Conklin made the final point that stem cell models are powerful because scientists can use them to screen and develop new drugs for diseases that have no treatments or cures. His lab is already working on identifying new drugs for heart disease using human induced pluripotent stem cells derived from patients with cardiomyopathy.

Scientists and Patient Advocates Speak Out

Malin Parmar, Lund University

Malin Parmar, Lund University

The first scientist to speak was Malin Parmar, a Professor at Lund University. She discussed the history of stem cell development for clinical trials in Parkinson’s disease (PD). Her team is launching the first in-human trial for Parkinson’s using cells derived from human pluripotent stem cells in 2016. After Parmar’s talk, John Lipp, a PD patient advocate. He explained that while he might look normal standing in front of the crowd, his PD symptoms vary wildly throughout the day and make it hard for him to live a normal life. He believes in the work that scientists like Parmar are doing and confidently said, “In my lifetime, we will find a stem cell cure for Parkinson’s disease.”

Adrienne Shapiro, Patient Advocate

Adrienne Shapiro, Patient Advocate

The next scientist to speak was UCLA Professor Donald Kohn. He discussed his lab’s latest efforts to develop stem cell treatments for different blood disorder diseases. His team is using gene therapy to modify blood stem cells in bone marrow to treat and cure babies with SCID, also known as “bubble-boy disease”. Kohn also mentioned their work in sickle cell disease (SCD) and in chronic granulomatous disease, both of which are now in CIRM-funded clinical trials. He was followed by Adrienne Shapiro, a patient advocate and mother of a child with SCD. Adrienne gave a passionate and moving speech about her family history of SCD and her battle to help find a cure for her daughter. She said “nobody plans to be a patient advocate. It is a calling born of necessity and pain. I just wanted my daughter to outlive me.”

Henry Klassen (UC Irvine)

Henry Klassen, UC Irvine

Henry Klassen, a professor at UC Irvine, next spoke about blinding eye diseases, specifically retinitis pigmentosa (RP). This disease damages the photo receptors in the back of the eye and eventually causes blindness. There is no cure for RP, but Klassen and his team are testing the safety of transplanting human retinal progenitor cells in to the eyes of RP patients in a CIRM-funded Phase 1/2 clinical trial.

Kristen MacDonald, RP patient

Kristen MacDonald, RP patient

RP patient, Kristen MacDonald, was the trial’s first patient to be treated. She bravely spoke about her experience with losing her vision. She didn’t realize she was going blind until she had a series of accidents that left her with two broken arms. She had to reinvent herself both physically and emotionally, but now has hope that she might see again after participating in this clinical trial. She said that after the transplant she can now finally see light in her bad eye and her hope is that in her lifetime she can say, “One day, people used to go blind.”

Lastly, Catriona Jamieson, a professor and Alpha Stem Cell Clinic director at UCSD, discussed how she is trying to develop new treatments for blood cancers by eradicating cancer stem cells. Her team is conducting a Phase 1 CIRM-funded clinical trial that’s testing the safety of an antibody drug called Cirmtuzumab in patients with chronic lymphocytic leukemia (CLL).

Scientists and Patients need to work together

Don Kohn, Catriona Jamieson, Malin Parmar

Don Kohn, Catriona Jamieson, Malin Parmar

At the end of the night, the scientists and patient advocates took the stage to answer questions from the audience. A patient advocate in the audience asked, “How can we help scientists develop treatments for patients more quickly?”

The scientists responded that stem cell research needs more funding and that agencies like CIRM are making this possible. However, we need to keep the momentum going and to do that both the physicians, scientists and patient advocates need to work together to advocate for more support. The patient advocates in the panel couldn’t have agreed more and voiced their enthusiasm for working together with scientists and clinicians to make their hopes for cures a reality.

The CIRM public event was a huge success and brought in more than 150 people, many of whom stayed after the event to ask the panelists more questions. It was a great kick off for the ISSCR conference, which starts today. For coverage, you can follow the Stem Cellar Blog for updates on interesting stem cell stories that catch our eye.

CIRM Public Stem Cell Event

CIRM Public Stem Cell Event

Helping stem cells sleep can boost their power to heal

Mouse muscle

Mighty mouse muscle cells

We are often told that sleep is one of the most important elements of a healthy lifestyle, that it helps in the healing and repair of our heart and blood vessels – among other things.

It turns out that sleep, or something very similar, is equally important for stem cells, helping them retain their power or potency, which is a measure of their effectiveness and efficiency in generating the mature adult cells that are needed to repair damage. Now researchers from Stanford, with a little help from CIRM, have found a way to help stem cells get the necessary rest before kicking in to action. This could pave the way for a whole new approach to treating a variety of genetic disorders such as muscular dystrophy.

Inside out

One problem that has slowed down the development of stem cell therapies has been the inability to manipulate stem cells outside of the body, without reducing their potency. In the body these cells can remain quiescent or dormant for years until called in to action to repair an injury. That’s because they are found in a specialized environment or niche, one that has very particular physical, chemical and biological properties. However, once the stem cells are removed from that niche and placed in a dish in the lab they become active and start proliferating and changing into other kinds of cells.

You might think that’s good, because we want those stem cells to change and mature, but in this case we don’t, at least not yet. We want them to wait till we return them to the body to do their magic. Changing too soon means they have less power to do that.

Researchers at Stanford may have found a way to stop that happening, by creating an environment in the lab that more closely resembles that in the body, so the stem cells remain dormant longer.

As senior author, Thomas Rando, said in a Stanford news release, they have found a way to keep the stem cells dormant longer:

Dr. Thomas Rando, Stanford

Dr. Thomas Rando, Stanford

“Normally these stem cells like to cuddle right up against their native muscle fibers. When we disrupt that interaction, the cells are activated and begin to divide and become less stemlike. But now we’ve designed an artificial substrate that, to the cells, looks, smells and feels like a real muscle fiber. When we also bathe these fibers in the appropriate factors, we find that the stem cells maintain high-potency and regenerative capacity.”

Creating an artificial home

When mouse muscle stem cells (MuSCs) are removed from the mouse they lose their potency after just two days. So the Stanford team set out to identify what elements in the mouse niche helped the cells remain dormant. They identified the molecular signature of the quiescent MuSCs and used that to help screen different compounds to see which ones could help keep those cells dormant, even after they were removed from the mouse and collected in a lab dish.

They whittled down the number of potential compounds involved in this process from 50 to 10, and then tested these in different combinations until they found a formulation that kept the stem cells quiescent for at least 2 days outside of the mouse.

But that was just the start. Next they experimented with different kinds of engineered muscle fibers, to simulate the physical environment inside the mouse niche. After testing various materials, they found that the one with the greatest elasticity was the most effective and used that to create a kind of scaffold for the stem cells.

The big test

The artificial niche they created clearly worked in helping keep the MuSCs in a dormant state outside of the mouse. But would they work when transplanted back into the mouse? To answer this question they tested these stem cells to see if they retained their ability to self-renew and to change into other kinds of cells in the mouse. The good news is they did, and were far more effective at both than MuSCs that had not been stored in the artificial niche.

So, great news for mice but what about people, would this same approach work with human muscle stem cells (hMuSCs)? They next tested this approach using hMuSCs and found that the hMuSCs cultured on the artificial niche were more effective at both self-renewal and retaining their potency than hMuSCs kept in more conventional conditions, at least in the lab.

In the study, published in the journal Nature Biotechnology, the researchers say this finding could help overcome some of the challenges that have slowed down the development of effective therapies:

“Research on MuSCs, hematopoietic stem cells and neural stem cells has shown that very small numbers of quiescent stem cells, even single cells, can replace vast amounts of tissue; culture systems that that maintain stem cell quiescence may allow these findings to be translated to clinical practice. In addition, the possibility of culturing hMuSCs for longer time periods without loss of potency in order to correct mutations associated with genetic disorders, such as muscular dystrophy, followed by transplantation of the corrected cells to replace the pathogenic tissue may enable improved stem cell therapeutics for muscle disorders.”

Embryos with abnormal chromosomes can repair themselves


In a chorionic villus sampling (CVS) test, cells from the fetal side of the placenta are collected and tests for genetic defects.
Image credit: ADAM Health Solutions

Like an increasing number of women, Magdalena Zernicka-Goetz waited later in life to have kids and was pregnant at 44 with her second child. Because older moms have an increased risk of giving birth to children with genetic disorders, Zernicka-Goetz opted to have an early genetic screening test about 12 weeks into her pregnancy. The test, which looks for irregular amounts of chromosomes in the cells taken from the placenta, showed that a quarter of the cells in the developing fetus had genetic abnormalities.

Expectant mothers and tough choices

If she carried the child to term, would the baby have a birth defect? Zernicka-Goetz learned from geneticists that this question was difficult to answer due to a lack of data about what happens to abnormal cells in the developing fetus. Fortunately, her baby was born happy and healthy. But the experience motivated her to seek out a better understanding for the sake of other women who would be faced with similar difficult decisions based on screening tests.

As a professor of developmental biology at Cambridge University, Zernicka-Geotz had the expertise to follow through on this challenge. And in a Nature Communications journal article published yesterday, she and her team report a fascinating result: the very early embryo has the ability to essentially repair itself by getting rid of abnormal cells.

Aneuploidy: You Have the Wrong Number


Aneuploidy in the developing fetus can lead to genetic disorders. Image credit: Deluca Lab Colorado State University

To reach this finding, the team first had to recreate chromosomal abnormalities in mouse embryos. If you remember your high school or college biology, you’ll recall that before a cell divides, it duplicates each chromosome and then each resulting “daughter” cell grabs one chromosome copy using a retracting spindle fiber structure. The scientists took advantage of the fact that treating dividing cells with the drug reversine destabilizes the spindle fibers and in turn causes an unequal divvying up of the chromosomes between the daughter cells. In scientific jargon the condition is called aneuploidy.

Rescuing the embryo by cellular suicide

Blog embryo repair fig 3

Generating early mouse embryos with an equal mix of normal cells and cells with abnormal chromosome numbers (induced via reversine treatment). Image credit: Bolton et al. Nat Commun. 2016 Mar 29;7:11165

The researchers created mosaic embryos at the eight cell stage in which half the cells had a normal set of chromosomes while the other half we’re the reversine-treated cells with abnormal numbers of chromosomes. With these genetically mosaic embryos, the team tagged the cells with fluorescent dye and used time-lapsed imaging to track the fate of each cell for 48 hours. They found a decrease specifically in the portion of cells that stemmed from the abnormal cells.

A follow up experiment examined cell death as a way to help explain the reduced number of abnormal cells. The researchers found that compared to the normal set of cells in the embryo, the abnormal cells had a significantly higher evidence of apoptosis, or programmed cell death, a natural process that occurs to eliminate harmful or damaged cells. According to Zernicka-Geota and the team, this is the first study to directly show the elimination of abnormal cells in the growing embryo.

Screen Shot 2016-03-30 at 11.25.43 AM.png

Time lapse images showing an abnormal cell (green cell indicated by arrow) being eliminated by apoptosis (programmed cell death) and then engulfed by normal (red) cells (engulfment indicated by star).
Image credit: Bolton et al. Nat Commun. 2016 Mar 29;7:11165

To look at their fate beyond the very early stages of development, the mosaic mouse embryos were implanted into foster mothers and allowed to develop to full term. Thirteen of the twenty-six embryos transferred to foster mothers gave rise to live pups which were all healthy after four months of age.

As Zermicka-Geota stated in a university press release picked up by Medical Express, if these findings reflect what goes on in human development, then decisions based on genetic screening results may not be clear cut:

“We found that even when half of the cells in the early stage embryo are abnormal, the embryo can fully repair itself. It will mean that even when early indications suggest a child might have a birth defect because there are some, but importantly not all abnormal cells in its embryonic body, this isn’t necessarily the case.”

Implications for genetic testing on days-old IVF embryos

These new results don’t suggest that current genetic testing is obsolete. For instance, the amniocentesis test, which collects fetal tissue from the mother’s amniotic fluid between 14 and 20 weeks of pregnancy, can detect genetic disorders with 98-99% accuracy. But this study may have important implications for testing done much earlier. When couples conceive via in vitro fertilization, a so-called pre-implantation genetic diagnosis (PGD) test can be performed on embryos that are only a few days old. In the test, a single cell is removed – without damaging the embryo – and the cell is tested for chromosomal defects. Based on this study, a positive PGD test may be misleading if that abnormal cell was destined to be eliminated from the embryo.

Rare disease underdogs come out on top at CIRM Board meeting


It seems like an oxymoron but one in ten Americans has a rare disease. With more than 7,000 known rare diseases it’s easy to see how each one could affect thousands of individuals and still be considered a rare or orphan condition.

Only 5% of rare diseases have FDA approved therapies

rare disease

(Source: Sermo)

People with rare diseases, and their families, consider themselves the underdogs of the medical world because they often have difficulty getting a proper diagnosis (most physicians have never come across many of these diseases and so don’t know how to identify them), and even when they do get a diagnosis they have limited treatment options, and those options they do have are often very expensive.  It’s no wonder these patients and their families feel isolated and alone.

Rare diseases affect more people than HIV and Cancer combined

Hopefully some will feel less isolated after yesterday’s CIRM Board meeting when several rare diseases were among the big winners, getting funding to tackle conditions such as ALS or Lou Gehrig’s disease, Severe Combined Immunodeficiency or SCID, Canavan disease, Tay-Sachs and Sandhoff disease. These all won awards under our Translation Research Program except for the SCID program which is a pre-clinical stage project.

As CIRM Board Chair Jonathan Thomas said in our news release, these awards have one purpose:

“The goal of our Translation program is to support the most promising stem cell-based projects and to help them accelerate that research out of the lab and into the real world, such as a clinical trial where they can be tested in people. The projects that our Board approved today are a great example of work that takes innovative approaches to developing new therapies for a wide variety of diseases.”

These awards are all for early-stage research projects, ones we hope will be successful and eventually move into clinical trials. One project approved yesterday is already in a clinical trial. Capricor Therapeutics was awarded $3.4 million to complete a combined Phase 1/2 clinical trial treating heart failure associated with Duchenne muscular dystrophy with its cardiosphere stem cell technology.  This same Capricor technology is being used in an ongoing CIRM-funded trial which aims to heal the scarring that occurs after a heart attack.

Duchenne muscular dystrophy (DMD) is a genetic disorder that is marked by progressive muscle degeneration and weakness. The symptoms usually start in early childhood, between ages 3 and 5, and the vast majority of cases are in boys. As the disease progresses it leads to heart failure, which typically leads to death before age 40.

The Capricor clinical trial hopes to treat that aspect of DMD, one that currently has no effective treatment.

As our President and CEO Randy Mills said in our news release:

Randy Mills, Stem Cell Agency President & CEO

Randy Mills, Stem Cell Agency President & CEO

“There can be nothing worse than for a parent to watch their child slowly lose a fight against a deadly disease. Many of the programs we are funding today are focused on helping find treatments for diseases that affect children, often in infancy. Because many of these diseases are rare there are limited treatment options for them, which makes it all the more important for CIRM to focus on targeting these unmet medical needs.”

Speaking on Rare Disease Day (you can read our blog about that here) Massachusetts Senator Karen Spilka said that “Rare diseases impact over 30 Million patients and caregivers in the United States alone.”

Hopefully the steps that the CIRM Board took yesterday will ultimately help ease the struggles of some of those families.

Rare Disease Day, a chance to raise awareness and hope.


Battling a deadly disease like cancer or Alzheimer’s is difficult; but battling a rare and deadly disease is doubly so. At least with common diseases there is a lot of research seeking to develop new treatments. With rare diseases there is often very little research, and so there are fewer options for treatment. Even just getting a diagnosis can be hard because most doctors may never have heard about, let alone seen, a case of a disease that only affects a few thousand individuals.

That’s why the last day of February, every year, has been designated Rare Disease Day.  It’s a time to raise awareness amongst the public, researchers, health  professionals and policy makers about the impact these diseases have on the lives of those affected by them. This means not just the individual with the problem, but their family and friends too.

There are nearly 7,000 diseases in the U.S. that are considered rare, meaning they affect fewer than 200,000 people at any given time.

No numbers no money

The reason why so many of these diseases have so few treatment options is obvious. With diseases that affect large numbers of people a new treatment or cure stands to make the company behind it a lot of money. With diseases that affect very small numbers of people the chances of seeing any return on investment are equally small.

Fortunately at CIRM we don’t have to worry about making a profit, all we are concerned with is accelerating stem cell treatments to patients with unmet medical needs. And in the case of people with rare diseases, those needs are almost invariably unmet.

That’s why over the years we have invested heavily in diseases that are often overlooked because they affect relatively small numbers of people. In fact right now we are funding clinical trials in several of these including sickle cell anemia, retinitis pigmentosa and chronic granulomatous disease. We are also funding work in conditions like Huntington’s disease, ALS or Lou Gehrig’s disease, and SCID or “bubble baby” disease.

Focus on the people

As in everything we do our involvement is not just about funding research – important as that is – it’s also about engaging with the people most affected by these diseases, the patient advocate community. Patient advocates help us in several ways:

  • Collaborating with us and other key stakeholders to try and change the way the Food and Drug Administration (FDA) works. Our goal is to create an easier and faster, but no less safe, method of approving the most promising stem cell therapies for clinical trial. With so few available treatments for rare diseases having a smoother route to a clinical trial will benefit these communities.
  • Spreading the word to researchers and companies about CIRM 2.0, our new, faster and more streamlined funding opportunities to help us move the most promising therapies along as fast as possible. The good news is that this means anyone, anywhere can apply for funding. We don’t care how many people are affected by a disease, we only care about the quality of the proposed research project that could help them.
  • Recruiting Patient Advocates to our Clinical Advisory Panels (CAPs), teams that we assign to each project in a clinical trial to help guide and inform the researchers at every stage of their work. This not only gives each project the best possible chance of succeeding but it also helps the team stay focused on the mission, of saving, and changing, people’s lives.
  • Helping us recruit patients for clinical trials. The inability to recruit and retain enough patients to meet a project’s enrollment requirements is one of the biggest reasons many clinical trials fail. This is particularly problematic for rare diseases. By using Patient Advocates to increase our ability to enroll and retain patients we will increase the likelihood a clinical trial is able to succeed.

Organizing to fight back

There are some great organizations supporting and advocating on behalf of families affected by rare diseases, such as the EveryLife Foundation  and the National Organization for Rare Diseases (NORD).  They are working hard to raise awareness about these diseases, to get funding to do research, and to clear away some of the regulatory hurdles researchers face in being able to move the most promising therapies out of the lab and into clinical trials where they can be tested on people.

For the individuals and families affected by conditions like beta thalassemia and muscular dystrophy – potentially fatal genetic disorders – every day is Rare Disease Day. They live with the reality of these problems every single day. That’s why we are committed to working hard every single day, to find a treatment that can help them and their loved ones.

Timing is everything: could CRISPR gene editing push CIRM to change its rules on funding stem cell research?


Talk about timely. When we decided, several months ago, to hold a Standards Working Group (SWG) meeting to talk about the impact of CRISPR, a tool that is transforming the field of human gene editing, we had no idea that our meeting would fall smack in the midst of a flurry of news stories about the potential, but also the controversy, surrounding this approach.

Within a few days of our meeting lawmakers in the UK had approved the use of CRISPR for gene editing in human embryos for fertility research —a controversial first step toward what some see as a future of designer babies. And a U.S. Food and Drug Advisory report said conducting mitochondrial therapy research on human embryos is “ethically permissible”, under very limited conditions.

So it was clear from the outset that the SWG meeting was going to be touching on some fascinating and fast moving science that was loaded with ethical, social and moral questions.

Reviewing the rules

The goal of the meeting was to see if, in the light of advances with tools like CRISPR, we at CIRM needed to make any changes to our rules and regulations regarding the funding of this kind of work. We already have some strong guidelines in place to help us determine if we should fund work that involves editing human embryos, but are they strong enough?

There were some terrific speakers – including Nobel Prize winner Dr. David Baltimore; Alta Charo, a professor of Law and Bioethics at the University of Wisconsin-Madison  ; and Charis Thompson, chair of the Center for the Science, Technology, and Medicine in Society at the University of California, Berkeley – who gave some thought-provoking presentations. And there was also a truly engaged audience who offered some equally thought provoking questions.

CIRM Board member Jeff Sheehy highlighted how complex and broad ranging the issues are when he posed this question:

“Do we need to think about the rights of the embryo donor? If they have a severe inheritable disease and the embryo they donated for research has been edited, with CRISPR or other tools, to remove that potential do they have a right to know about that or even access to that technology for their own use?”

Alta Charo said this is not just a question for scientists, but something that could potentially affect everyone and so there is a real need to engage as many groups as possible in discussing it:

“How and to what extent do you involve patient advocates, members of the disability rights community and social justice community – racial or economic or geographic.  This is why we need these broader conversations, so we include all perspectives as we attempt to draw up guidelines and rules and regulations.”

It quickly became clear that the discussion was going to be even more robust than we imagined, and the issues raised were too many and too complex for us to hope to reach any conclusions or produce any recommendations in one day.

As Bernie Lo, President of the Greenwall Foundation in New York, who chaired the meeting said:

“We are not going to resolve these issues today, in fact what we have done is uncover a lot more issues and complexity.”

Time to ask tough questions

In the end it was decided that the most productive use of the day was not to limit the discussion at the workshop but to get those present to highlight the issues and questions that were most important and leave it to the SWG to then work through those and develop a series of recommendations that would eventually be presented to the CIRM Board.

The questions to be answered included but were not limited to:

1) Do we need to reconsider the language used in getting informed consent from donors in light of the ability of CRISPR and other technologies to do things that we previously couldn’t easily do?

2) Can we use CRISPR on previously donated materials/samples where general consent was given without knowing that these technologies could be available or can we only use it on biomaterials to be collected going forward?

3) Clarify whether the language we use about genetic modification should also include mitochondrial DNA as well as nuclear DNA.

4) What is the possibility that somatic or adult cell gene editing may lead to inadvertent germ line editing (altering the genomes of eggs and sperm will pass on these genetic modifications to the next generation).

5) How do we engage with patient advocates and other community groups such as the social justice and equity movements to get their input on these topics? Do we need to do more outreach and education among the public or specific groups and try to get more input from them (after all we are a taxpayer created and funded organization so we clearly have some responsibility to the wider California community and not just to researchers and patients)?

6) As CIRM already funds human embryo research should we now consider funding the use of CRISPR and other technologies that can modify the human embryo provided those embryos are not going to be implanted in a human uterus, as is the case with the recently approved research in the UK.

Stay tuned, more to come!

This was a really detailed dive into a subject that is clearly getting a lot of scientific attention around the world, and is no longer an abstract idea but is rapidly becoming a scientific reality. The next step is for a subgroup of the SWG to put together the key issues at stake here and place them in a framework for another discussion with the full SWG at some future date.

Once the SWG has reached consensus their recommendations will then go to the CIRM Board for its consideration.

We will be sure to update you on this as things progress.

To modify, or not to modify: Experts discuss human germline modification at WSCS15

The question of whether human germline modification, or the genetic modification of human reproductive cells, should be allowed or banned was discussed by a panel of experts in the Ethics, Law and Society session during Day 1 of the World Stem Cell Summit.

On the panel were Aubrey de Grey, Chief Science Officer of the SENS Foundation, Paul Knoepfler, Associate Professor at the UC Davis school of medicine (and a CIRM grantee), and Aaron Levine, Associate Professor of Public Policy at Georgia Tech.

Aubrey de Grey, Paul Knoepfler, Aaron Levine

Aubrey de Grey, Paul Knoepfler, Aaron Levine

What Paul Knoepfler said…

On the basic research side, Paul discussed how CRISPR has revolutionized the way germline modification is being done from the older, costly, time-consuming method using homologous recombination to the faster, more efficient, and cheaper gene editing technology that is CRISPR.

In the big picture, he said that, “people will pursue germline modification with a variety of different goals.” He further explained that because this will likely happen in the future, scientists need to consider the risks (off target effects to name one) and the societal and ethical impacts of this technology. Another question he said we should consider is, whether as a society, we support the modification of the germline for health or enhancement reasons.

He concluded with a recap of last week’s International Summit on Human Gene Editing saying that while the organizers didn’t put forth a definitive statement on whether there should be a moratorium on editing the human germline, he himself believes that there should be a temporary moratorium on the clinical use of this technology since the idea is still very controversial and there is no overall consensus within the scientific community.

What Aubrey de Grey said…

Aubrey began by saying that as a gerontologist, he is interested in all potential therapies that could postpone the effects of old age, many of which could involve genetic modification. He went on to say that it might not seem intuitive that editing the human germline would be applicable to fighting aging, but that:

“Even though the medical imperative to engaging genetic germline modification may seem to be less clear in the case of aging than it is for inherited diseases, which people are unequivocally agreed on that is a bad thing, never-the-less, the potential application to aging may actually play a significant role in the debate, because we’ve all got aging.”

He gave an example of the ApoE4 gene. If you have two copies of this form of the gene instead of the normal ApoE3 gene, then you have a very high risk of getting Alzheimer’s disease and atherosclerosis. He posed the question to the audience, asking them whether if they knew that they had this disease causing gene, would they consider genetically altering their fertilized eggs back into the safe ApoE3 version to prevent their offspring from inheriting disease even if the therapy wasn’t approved by the FDA. It’s a hard question to answer and Aubrey further commented that if we begin using genetic modification to prevent one disease, where would we draw the line and where would modification end?

He ended with saying that the real question we need to consider is “whether people will want to do germline modification against aging, even though the modifications may really be more in the way of enhancements than genuine therapies.”

What Aaron Levine said…

Aaron Levine began with saying that the question of human germline modification is an old question with new twists. By new twists he meant the recent advances in gene editing technologies like CRISPR and Zinc Finger Nucleases. He further commented that the baseline question of this debate is whether we should modify the DNA of the germline, and that how we do it isn’t as significant.

He played devil’s advocate by saying that germline editing would greatly benefit single gene disorders, but that we should think of the full spectrum. Many traits that we might want, we don’t know enough about and attempting to add or remove these traits using gene editing would be like shooting in the dark.

On policy side, Aaron commented that international policy harmonization would be nice, but that we should treat it skeptically. He said that not everyone is going to agree or follow the same rules and we need to consider this going forward. As for the FDA, he said that its role and regulations regarding germline editing aren’t clear and that these need to be defined.

One really interesting point he made was the issue of unproven stem cell clinics. They exist and pose a huge risk to human health. The real question, he said, is could this turn into unproven CRISPR clinics around the world? He ended with saying that someone will claim to offer this technology soon and asked what we should do about it.

From the peanut gallery…

One of the questions asked by the audience was whether it’s just a matter of time that one of the world’s governments might go forward with human germline modification because of the huge medical implications.

Paul responded first saying that there was a consensus at the gene editing summit that it’s more of a question of when, rather than if this would happen. Aaron agreed and said that he believed it would happen but wasn’t sure when, and followed with saying that the more important question is how it will be done, overseen, and what reasons the editing will be done for.

Bernie Siegel, who is the co-Chair of the World Stem Cell Summit, spoke at the end and said that the panel delivered exactly what he hoped it would. He emphasized a theme that I didn’t mention in this blog but that was brought up by each of the panelists: the voice of patients.

“One of the things missing from the [International Summit on Gene Editing] meeting was the voice of the patient community. Do they understand the concepts of CRISPR technology? Patients are a major stake holder group, and they have the most influence on creating change in policy. When we talk about a moratorium, the patients see it as a five-alarm fire. All they want is to see a few drips of water, and they can’t get it. From a societal and popular culture standpoint, these are a whole group of people that will be experiencing the sweeping changes of biotech today. When those voices that are receiving these technologies enter the conversation, it will be a full debate.”

Brain Stem Cells in a Dish to the Rescue


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The best way to impress your friends at the next party you attend might be to casually mention that scientists can grow miniature brain models in a dish using human stem cells. Sure, that might scare away some people, but when you explain how these tiny brain models can be used to study many different neurological diseases and could help identify new therapies to treat these diseases, your social status could sky rocket.

Recently, a group at UC San Diego used human stem cells to model a rare neurological disorder and identified a drug molecule that might be able to fix it. This work was funded in part by CIRM, and it was published today in the journal Molecular Psychiatry.

The disorder is called MECP2 duplication syndrome. It’s caused by a duplication of the MECP2 gene located in the X chromosome, and is genetically inherited as an X-linked disorder, meaning the disease is much more common in males. Having extra copies of this gene causes a number of unfortunate symptoms including reduced muscle tone (hypotonia), intellectual disabilities, impaired speech, seizures, and developmental delays, to name a few. So far, treatments for this disorder only help ease the symptoms and do not cure the disease.

The group from UCSD decided to model this disease using induced pluripotent stem cells (iPSCs) derived from patients with MECP2 duplication syndrome. iPSCs can form any cell type in the body, and the group used this to their advantage by coaxing the iPSCs into the specific type of nerve cell affected by the disorder. Their hard work was rewarded when they observed that the diseased nerve cells acted differently than normal nerve cells without the disease.

In fact, the diseased nerve cells generated more connections with other nearby nerve cells, and this altered their ability to talk to each other and perform their normal functions. The senior author Alysson Muotri described the difference as an “over-synchronization of the neuronal networks”, meaning that they were more active and tended to fire their signals in unison.

After establishing a relevant nerve cell model of MECP2 duplication disorder, the group tested out a library of drug molecules and identified a new drug candidate that was able to rescue the diseased nerve cells from their “over-synchronized” activity.

The senior author Alysson Muotri commented on the study in a press release:

Alysson Muotri (Photo by David Ahntholz)  

This work is encouraging for several reasons. First, this compound had never before been considered a therapeutic alternative for neurological disorders. Second, the speed in which we were able to do this. With mouse models, this work would likely have taken years and results would not necessarily be useful for humans.


The press release goes on to describe how Muotri and his team plan to push their preclinical studies using human stem-cell based models forward in hopes of entering clinical trials in the near future.


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