Partnering with the best to help find cures for rare diseases

As a state agency we focus most of our efforts and nearly all our money on California. That’s what we were set up to do. But that doesn’t mean we don’t also look outside the borders of California to try and find the best research, and the most promising therapies, to help people in need.

Today’s meeting of the CIRM Board was the first time we have had a chance to partner with one of the leading research facilities in the country focusing on children and rare diseases; St. Jude Children’s Researech Hospital in Memphis, Tennessee.

a4da990e3de7a2112ee875fc784deeafSt. Jude is getting $11.9 million to run a Phase I/II clinical trial for x-linked severe combined immunodeficiency disorder (SCID), a catastrophic condition where children are born without a functioning immune system. Because they are unable to fight off infections, many children born with SCID die in the first few years of life.

St. Jude is teaming up with researchers at the University of California, San Francisco (UCSF) to genetically modify the patient’s own blood stem cells, hopefully creating a new blood system and repairing the damaged immune system. St. Jude came up with the method of doing this, UCSF will treat the patients. Having that California component to the clinical trial is what makes it possible for us to fund this work.

This is the first time CIRM has funded work with St. Jude and reflects our commitment to moving the most promising research into clinical trials in people, regardless of whether that work originates inside or outside California.

The Board also voted to fund researchers at Cedars-Sinai to run a clinical trial on ALS or Lou Gehrig’s disease. Like SCID, ALS is a rare disease. As Randy Mills, our President and CEO, said in a news release:

CIRM CEO and President, Randy Mills.

CIRM CEO and President, Randy Mills.

“While making a funding decision at CIRM we don’t just look at how many people are affected by a disease, we also look at the severity of the disease on the individual and the potential for impacting other diseases. While the number of patients afflicted by these two diseases may be small, their need is great. Additionally, the potential to use these approaches in treating other disease is very real. The underlying technology used in treating SCID, for example, has potential application in other areas such as sickle cell disease and HIV/AIDS.”

We have written several blogs about the research that cured children with SCID.

The Board also approved funding for a clinical trial to develop a treatment for type 1 diabetes (T1D). This is an autoimmune disease that affects around 1.25 million Americans, and millions more around the globe.

T1D is where the body’s own immune system attacks the cells that produce insulin, which is needed to control blood sugar levels. If left untreated it can result in serious, even life-threatening, complications such as vision loss, kidney damage and heart attacks.

Researchers at Caladrius Biosciences will take cells, called regulatory T cells (Tregs), from the patient’s own immune system, expand the number of those cells in the lab and enhance them to make them more effective at preventing the autoimmune attack on the insulin-producing cells.

The focus is on newly-diagnosed adolescents because studies show that at the time of diagnosis T1D patients usually have around 20 percent of their insulin-producing cells still intact. It’s hoped by intervening early the therapy can protect those cells and reduce the need for patients to rely on insulin injections.

David J. Mazzo, Ph.D., CEO of Caladrius Biosciences, says this is hopeful news for people with type 1 diabetes:

David Mazzo

David Mazzo

“We firmly believe that this therapy has the potential to improve the lives of people with T1D and this grant helps us advance our Phase 2 clinical study with the goal of determining the potential for CLBS03 to be an effective therapy in this important indication.”

 


Related Links:

Rare diseases are not so rare

brenden-and-dog

Brenden Whittaker – cured in a CIRM-funded clinical trial focusing on his rare disease

It seems like a contradiction in terms to say that there are nearly 7,000 diseases, affecting 30 million people, that are considered rare in the US. But the definition of a rare disease is one that affects fewer than 200,000 people and the National Institutes of Health’s (NIH) Genetic and Rare Diseases Information Center (GARD) has a database that lists every one of them.

Those range from relatively well known conditions such as sickle cell disease and cerebral palsy, to lesser known ones such as attenuated familial adenomatous polyposis (AFAP) – an inherited condition that increases your risk of colon cancer.

Because disease like these are so rare, in the past many individuals with them felt isolated and alone. Thanks to the internet, people are now able to find online support groups where they can get advice on coping strategies, ideas on potential therapies and, just as important, can create a sense of community.

One of the biggest problems facing the rare disease community is a lack of funding for research to develop treatments or cures. Because these diseases affect fewer than 200,000 people most pharmaceutical companies don’t invest large sums of money developing treatments; they simply wouldn’t be able to get a big enough return on their investment. This is not a value judgement. It’s just a business reality.

And that’s where CIRM comes in. We were created, in part, to help those who can’t get help from other sources. This week alone, for example, our governing Board is meeting to vote on funding clinical trials for two rare and deadly diseases – ALS or Lou Gehrig’s disease, and Severe Combined Immunodeficiency or SCID. This kind of funding can mean the difference between life and death.

cirm-2016-annual-report-web-12

For proof, you need look no further than Evie Vaccaro, the young girl we feature on the front of our 2016 Annual Report. Evie was born with SCID and faced a bleak future. But UCLA researcher Don Kohn, with some help from CIRM, developed a therapy that cured Evie. This latest clinical trial could help make a similar therapy available to other children with SCID.

But with almost 7,000 rare diseases it’s clear we can’t help everyone. In fact, there are only around 450 FDA-approved therapies for all these conditions. That’s why the National Organization for Rare Disorders (NORD) and groups like them are organizing events around the US on February 28th, which has been designated as Rare Disease Day. The goal is to raise awareness about rare diseases, and to advocate for action to help this community. Here’s a link to Advocacy Events in different states around the US.

Alone, each of these groups is small and easily overlooked. Combined they have a powerful voice, 30 million strong, that demands to be heard.

 

 

Stories that caught our eye: stem cell transplants help put MS in remission; unlocking the cause of autism; and a day to discover what stem cells are all about

multiple-sclerosis

Motor neurons

Stem cell transplants help put MS in remission: A combination of high dose immunosuppressive therapy and transplant of a person’s own blood stem cells seems to be a powerful tool in helping people with relapsing-remitting multiple sclerosis (RRMS) go into sustained remission.

Multiple sclerosis (MS) is an autoimmune disorder where the body’s own immune system attacks the brain and spinal cord, causing a wide variety of symptoms including overwhelming fatigue, blurred vision and mobility problems. RRMS is the most common form of MS, affecting up to 85 percent of people, and is characterized by attacks followed by periods of remission.

The HALT-MS trial, which was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), took the patient’s own blood stem cells, gave the individual chemotherapy to deplete their immune system, then returned the blood stem cells to the patient. The stem cells created a new blood supply and seemed to help repair the immune system.

Five years after the treatment, most of the patients were still in remission, despite not taking any medications for MS. Some people even recovered some mobility or other capabilities that they had lost due to the disease.

In a news release, Dr. Anthony Fauci, Director of NIAID, said anything that holds the disease at bay and helps people avoid taking medications is important:

“These extended findings suggest that one-time treatment with HDIT/HCT may be substantially more effective than long-term treatment with the best available medications for people with a certain type of MS. These encouraging results support the development of a large, randomized trial to directly compare HDIT/HCT to standard of care for this often-debilitating disease.”

scripps-campus

Scripps Research Institute

Using stem cells to model brain development disorders. (Karen Ring) CIRM-funded scientists from the Scripps Research Institute are interested in understanding how the brain develops and what goes wrong to cause intellectual disabilities like Fragile X syndrome, a genetic disease that is a common cause of autism spectrum disorder.

Because studying developmental disorders in humans is very difficult, the Scripps team turned to stem cell models for answers. This week, in the journal Brain, they published a breakthrough in our understanding of the early stages of brain development. They took induced pluripotent stem cells (iPSCs), made from cells from Fragile X syndrome patients, and turned these cells into brain cells called neurons in a cell culture dish.

They noticed an obvious difference between Fragile X patient iPSCs and healthy iPSCs: the patient stem cells took longer to develop into neurons, a result that suggests a similar delay in fetal brain development. The neurons from Fragile X patients also had difficulty forming synaptic connections, which are bridges that allow for information to pass from one neuron to another.

Scripps Research professor Jeanne Loring said that their findings could help to identify new drug therapies to treat Fragile X syndrome. She explained in a press release;

“We’re the first to see that these changes happen very early in brain development. This may be the only way we’ll be able to identify possible drug treatments to minimize the effects of the disorder.”

Looking ahead, Loring and her team will apply their stem cell model to other developmental diseases. She said, “Now we have the tools to ask the questions to advance people’s health.”

A Day to Discover What Stem Cells Are All about.  (Karen Ring) Everyone is familiar with the word stem cells, but do they really know what these cells are and what they are capable of? Scientists are finding creative ways to educate the public and students about the power of stem cells and stem cell research. A great example is the University of Southern California (USC), which is hosting a Stem Cell Day of Discovery to educate middle and high school students and their families about stem cell research.

The event is this Saturday at the USC Health Sciences Campus and will feature science talks, lab tours, hands-on experiments, stem cell lab video games, and a resource fair. It’s a wonderful opportunity for families to engage in science and also to expose young students to science in a fun and engaging way.

Interest in Stem Cell Day has been so high that the event has already sold out. But don’t worry, there will be another stem cell day next year. And for those of you who don’t live in Southern California, mark your calendars for the 2017 Stem Cell Awareness Day on Wednesday, October 11th. There will be stem cell education events all over California and in other parts of the country during that week in honor of this important day.

 

 

Stem cell stories that caught our eye: glowing stem cells and new insights into Zika and SCID

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.

Glowing stem cells help scientists understand how cells work. (Karen Ring)
It’s easy to notice when something is going wrong. It’s a lot harder to notice when something is going right. The same thing can be said for biology. Scientists dedicate their careers to studying unhealthy cells, trying to understand why people get certain diseases and what’s going wrong at the cellular level to cause these problems. But there is a lot to be said for doing scientific research on healthy cells so that we can better understand what’s happening when cells start to malfunction.

A group from the Allen Institute for Cell Science is doing just this. They used a popular gene-editing technology called CRISPR/Cas9 to genetically modify human stem cell lines so that certain parts inside the cell will glow different colors when observed under a fluorescent microscope. Specifically, the scientists inserted the genetic code to produce fluorescent proteins in both the nucleus and the mitochondria of the stem cells. The final result is a tool that allows scientists to study how stem cells specialize into mature cells in various tissues and organs.

Glowing human stem cells. The edges of the cells are shown in purple while the DNA in the cell’s nucleus is in blue. (Allen Institute for Cell Science).

Glowing human stem cells. The edges of the cells are shown in purple while the DNA in the cell’s nucleus is in blue. (Allen Institute for Cell Science).

The director of stem cells and gene editing at the Allen Institute, Ruwanthi Gunawardane, explained how their technology improves upon previous methods for getting cells to glow in an interview with Forbes:

 “We’re trying to understand how the cell behaves, how it functions, but flooding it with some external protein can really mess it up. The CRISPR system allows us to go into the DNA—the blueprint—and insert a gene that allows the cell to express the protein in its normal environment. Then, through live imaging, we can watch the cell and understand how it works.”

The team has made five of these glowing stem cell lines available for use by the scientific community through the Coriell Institute for Medical Research (which also works closely with the CIRM iPSC Initiative). Each cell line is unique and has a different cellular structure that glows. You can learn more about these cell lines on the Coriell Allen Institute webpage and by watching this video:

 

Zika can take multiple routes to infect a child’s brain. (Kevin McCormack)
One of the biggest health stories of 2016 has been the rapid, indeed alarming, spread of the Zika virus. It went from an obscure virus to a global epidemic found in more than 70 countries.

The major concern about the virus is its ability to cause brain defects in the developing brain. Now researchers at Harvard have found that it can do this in more ways than previously believed.

Up till now, it was believed that Zika does its damage by grabbing onto a protein called AXL on the surface of brain cells called neural progenitor cells (NPCs). However, the study, published in the journal Cell Stem Cell, showed that even when AXL was blocked, Zika still managed to infiltrate the brain.

Using induced pluripotent stem cell technology, the researchers were able to create NPCs and then modify them so they had no AXL expression. That should, in theory, have been able to block the Zika virus. But when they exposed those cells to the virus they found they were infected just as much as ordinary brain cells exposed to the virus were.

Caption: Zika virus (light blue) spreads through a three-dimensional model of a developing brain. Image by Max Salick and Nathaniel Kirkpatrick/Novartis

Caption: Zika virus (light blue) spreads through a three-dimensional model of a developing brain. Image by Max Salick and Nathaniel Kirkpatrick/Novartis

In a story in the Harvard Gazette, Kevin Eggan, one of the lead researchers, said this shows scientists need to re-think their approach to countering the virus:

“Our finding really recalibrates this field of research because it tells us we still have to go and find out how Zika is getting into these cells.”

 

Treatment for a severe form of bubble baby disease appears on the horizon. (Todd Dubnicoff)
Without treatment, kids born with bubble baby disease typically die before reaching 12 months of age. Formally called severe combined immunodeficiency (SCID), this genetic blood disorder leaves infants without an effective immune system and unable to fight off even minor infections. A bone marrow stem cell transplant from a matched sibling can treat the disease but this is only available in less than 20 percent of cases and other types of donors carry severe risks.

In what is shaping up to be a life-changing medical breakthrough, a UCLA team has developed a stem cell/gene therapy treatment that corrects the SCID mutation. Over 40 patients have participated to date with a 100% survival rate and CIRM has just awarded the team $20 million to continue clinical trials.

There’s a catch though: other forms of SCID exist. The therapy described above treats SCID patients with a mutation in a gene responsible for producing a protein called ADA. But an inherited mutation in another gene called Artemis, leads to a more severe form of SCID. These Artemis-SCID infants have even less success with a standard bone marrow transplant compared to those with ADA-SCID. Artemis plays a role in DNA damage repair something that occurs during the chemo and radiation therapy sessions that are often necessary for blood marrow transplants. So Artemis-SCID patients are hyper-sensitive to the side of effects of standard treatments.

A recent study by UCSF scientists in Human Gene Therapy, funded in part by CIRM, brings a lot of hope to these Artemis-SCID patient. Using a similar stem cell/gene therapy method, this team collected blood stem cells from the bone marrow of mice with a form of Artemis-SCID. Then they added a good copy of the human Artemis gene to these cells. Transplanting the blood stem cells back to mice, restored their immune systems which paves the way for delivering this approach to clinic to also help the Artemis-SCID patients in desperate need of a treatment.

Stem cell agency funds clinical trials in three life-threatening conditions

strategy-wide

A year ago the CIRM Board unanimously approved a new Strategic Plan for the stem cell agency. In the plan are some rather ambitious goals, including funding ten new clinical trials in 2016. For much of the last year that has looked very ambitious indeed. But today the Board took a big step towards reaching that goal, approving three clinical trials focused on some deadly or life-threatening conditions.

The first is Forty Seven Inc.’s work targeting colorectal cancer, using a monoclonal antibody that can strip away the cancer cells ability to evade  the immune system. The immune system can then attack the cancer. But just in case that’s not enough they’re going to hit the tumor from another side with an anti-cancer drug called cetuximab. It’s hoped this one-two punch combination will get rid of the cancer.

Finding something to help the estimated 49,000 people who die of colorectal cancer in the U.S. every year would be no small achievement. The CIRM Board thought this looked so promising they awarded Forty Seven Inc. $10.2 million to carry out a clinical trial to test if this approach is safe. We funded a similar approach by researchers at Stanford targeting solid tumors in the lung and that is showing encouraging results.

Our Board also awarded $7.35 million to a team at Cedars-Sinai in Los Angeles that is using stem cells to treat pulmonary hypertension, a form of high blood pressure in the lungs. This can have a devastating, life-changing impact on a person leaving them constantly short of breath, dizzy and feeling exhausted. Ultimately it can lead to heart failure.

The team at Cedars-Sinai will use cells called cardiospheres, derived from heart stem cells, to reduce inflammation in the arteries and reduce blood pressure. CIRM is funding another project by this team using a similar  approach to treat people who have suffered a heart attack. This work showed such promise in its Phase 1 trial it’s now in a larger Phase 2 clinical trial.

The largest award, worth $20 million, went to target one of the rarest diseases. A team from UCLA, led by Don Kohn, is focusing on Adenosine Deaminase Severe Combined Immune Deficiency (ADA-SCID), which is a rare form of a rare disease. Children born with this have no functioning immune system. It is often fatal in the first few years of life.

The UCLA team will take the patient’s own blood stem cells, genetically modify them to fix the mutation that is causing the problem, then return them to the patient to create a new healthy blood and immune system. The team have successfully used this approach in curing 23 SCID children in the last few years – we blogged about it here – and now they have FDA approval to move this modified approach into a Phase 2 clinical trial.

So why is CIRM putting money into projects that it has either already funded in earlier clinical trials or that have already shown to be effective? There are a number of reasons. First, our mission is to accelerate stem cell treatments to patients with unmet medical needs. Each of the diseases funded today represent an unmet medical need. Secondly, if something appears to be working for one problem why not try it on another similar one – provided the scientific rationale and evidence shows it is appropriate of course.

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

“Our Board’s support for these programs highlights how every member of the CIRM team shares that commitment to moving the most promising research out of the lab and into patients as quickly as we can. These are very different projects, but they all share the same goal, accelerating treatments to patients with unmet medical needs.”

We are trying to create a pipeline of projects that are all moving towards the same goal, clinical trials in people. Pipelines can be horizontal as well as vertical. So we don’t really care if the pipeline moves projects up or sideways as long as they succeed in moving treatments to patients. And I’m guessing that patients who get treatments that change their lives don’t particularly

Stem cell stories that caught our eye: better bone marrow transplants, turbo charging anti-inflammatory stem cells and Zika’s weapons

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.

Three steps to better BMT.  Bone marrow stem cell transplants (BMT) save the lives of many thousands of patients every year, but they also kill a significant number of the blood stem cell transplantcancer and immune disorder patients the procedure is intended to save. In order to make room in the bone marrow for new blood-forming stem cells, you first have to get rid of most of the stem cells already there, and the radiation and chemotherapy to do this proves too toxic for some patients. Also, donor marrow can contain immune cells from the donor that can attack the recipient causing Graft Versus Host Disease (GVHD), which can also be fatal.

Add this all together and physicians tend to save BMT for the patients with the most life threatening forms of the diseases.  A CIRM-funded team at Stanford has developed a three-step process that seems to dramatically reduce all those risks potentially opening up the procedure to less-sick patients including patients with life-altering, but not life-threatening, autoimmune diseases such as lupus and less severe forms of multiple sclerosis.

Experimenting in mice, they first used an antibody that attaches to a marker on blood stem cells called c-kit. But by itself that antibody could not get rid of enough of the stem cells. So, they added a second agent that blocked another protein, CD47, on the surface of blood stem cells. With that protein blocked, the animals own immune cells called macrophages, could destroy the blood stem cells. Then to make the donor cells safer, they used a technology they had developed many years ago to remove any straggler immune cells from the donor stem cells, thus drastically eliminating the chances for GVHD.

judith shizuru

Shizuru

“If it works in humans like it did in mice, we would expect that the risk of death from blood stem cell transplant would drop from 20 percent to effectively zero,” said senior author Judith Shizuru in a university press release posted by HealthCanal.

She went on to compare blood stem cell transplants to planting a new field of crops saying they were looking for a better way to first clear the field for planting and then a better way to do the planting. CIRM funded the team to develop the method for use with Severe Combined Immune Deficiency (SCID). The team published the current mouse study in the journal Science Translational Medicine.

 

Building a better anti-inflammatory stem cell.  Of the more than 700 stem cell therapy clinical trials underway around the world, more than half use the type of stem cell called a mesenchymal stem cell (MSC) found in bone marrow and fat—in marrow it resides alongside the blood-forming stem cells. Some of those trials are tapping into MSC’s ability to build bone, cartilage and blood vessels, but many are counting on their strong anti-inflammatory properties to fight autoimmune diseases.

When MSCs find themselves in an environment with pro-inflammatory proteins they respond by producing anti-inflammatory proteins. To enhance that effect some teams have bathed their MSC’s in pro-inflammatory proteins before injecting them into patients, but the effect of those proteins wears off quickly. So, a team led by CIRM-funded researcher Todd McDevitt at the Gladstone Institutes in San Francisco has bioengineered a way to make the effect long term.

McDevitt,-Todd-14

Gladstone used a CIRM Research Leadership award to recruit McDevitt from Georgia Tech

They loaded the pro-inflammatory proteins onto sugar-based particles that they imbedded in the middle of clusters of MSCs. The bioengineered complex slowly releases the cues to the MSCs and they in turn produced the desired anti-inflammatory proteins in greater quantities and much longer than in any other experiment.

 “A patient taking anti-inflammatory medication may not have high enough levels of inflammation to trigger the cells. We engineered the MSCs to ensure that they are consistently activated, so they can reliably dampen the immune response for longer,” said McDevitt in an institute press release.

The team published their research in Stem Cells Translational Medicine.

 

Stem cells used to identify Zika’s weapon.  It has been difficult for researchers to think about how to stop the Zika virus’ havoc on fetal brains without knowing how the virus does

Zika Virus

its evil deed. Now, a team at the University of Southern California (USC) has used fetal stem cells to discover two proteins that seem to be Zika’s key weapons.

Viruses often hijack our normal cell processes to enhance their ability to multiply and at the same time do harm to the host. In this case, the two proteins named NS4A and NS4B play key roles in the cell path for normal cell growth and disposal of damaged cells. When exploited by the virus, the two proteins result in cells being destroyed and not replaced.

“Those two viral proteins are ultimately the target for therapy development,” said USC’s Jae Jung in an article posted by Kaiser Health News.

As is typical with this news source, the author goes on to provide considerable high quality background about the Zika outbreak and efforts to find a vaccine or therapy, in this case quoting experts from Texas Children’s Hospital and Baylor.

 

Cloning fact timeline.  With the 20th anniversary last month of the birth of Dolly the sheep, the first cloned mammal, cloning seems to be much in discussion these days. So for

dolly-the-sheep

science nerds who like to keep back up facts handy CNN published a timeline of key events starting with the 1952 Nobel-winning discovery that you could replace the nucleus of a frog’s egg with the nucleus from another cell and still get the egg to develop into a tadpole. And 22 events later, it ends in 2014 with the first use of using cloning techniques to create stem cells that matched an adult.

Advancing Stem Cell Research at the CIRM Bridges Conference

Where will stem cell research be in 10 years?

What would you say to patients who wanted stem cell therapies now?

What are the most promising applications for stem cell research?

Why is it important for the government to fund regenerative medicine?

These challenging and thought-provoking questions were posed to a vibrant group of undergraduate and masters-level students at this year’s CIRM Bridges to Stem Cell Research and Therapy conference.

Educating the next generation of stem cell scientists

The Bridges program is one of CIRM’s educational programs that offers students the opportunity to take coursework at California state schools and community colleges and conduct stem cell research at top universities and industry labs. Its goal is to train the next generation of stem cell scientists by giving them access to the training and skills necessary to succeed in this career path.

The Bridges conference is the highlight of the program and the culmination of the students’ achievements. It’s a chance for students to showcase the research projects they’ve been working on for the past year, and also for them to network with other students and scientists.

Bridges students participated in a networking pitch event about stem cell research.

Bridges students participated in a networking pitch event about stem cell research.

CIRM kicked off the conference with a quick and dirty “Stem Cell Pitch” networking event. Students were divided into groups, given one of the four questions above and tasked with developing a thirty second pitch that answered their question. They were only given ten minutes to introduce themselves, discuss the question, and pick a spokesperson, yet when each team’s speaker took the stage, it seemed like they were practiced veterans. Every team had a unique, thoughtful answer that was inspiring to both the students and to the other scientists in the crowd.

Getting to the clinic and into patients

The bulk of the Bridges conference featured student poster presentations and scientific talks by leading academic and industry scientists. The theme of the talks was getting stem cell research into the clinic and into patients with unmet medical needs.

Here are a few highlights and photos from the talks:

On the clinical track for Huntington’s disease

Leslie Thompson, Professor at UC Irvine, spoke about her latest research in Huntington’s disease (HD). She described her work as a “race against time.” HD is a progressive neurodegenerative disorder that’s associated with multiple social and physical problems and currently has no cure. Leslie described how her lab is heading towards the clinic with human embryonic stem cell-derived neural (brain) stem cells that they are transplanting into mouse models of HD. So far, they’ve observed positive effects in HD mice that received human neural stem cell transplants including an improvement in the behavioral and motor defects and a reduction in the accumulation of toxic mutant Huntington protein in their nerve cells.

Leslie Thompson

Leslie Thompson

Leslie noted that because the transplanted stem cells are GMP-grade (meaning their quality is suitable for use in humans), they have a clear path forward to testing their potential disease modifying activity in human clinical trials. But before her team gets to humans, they must take the proper regulatory steps with the US Food and Drug Administration and conduct further experiments to test the safety and proper dosage of their stem cells in other mouse models as well as test other potential GMP-grade stem cell lines.

Gene therapy for SCID babies

Morton Cowan, a pediatric immunologist from UC San Francisco, followed Leslie with a talk about his efforts to get gene therapy for SCID (severe combined immunodeficiency disease) off the bench into the clinic. SCID is also known as bubble-baby disease and put simply, is caused by a lack of a functioning immune system. SCID babies don’t have normal T and B immune cell function and as a result, they generally die of infection or other conditions within their first year of life.

Morton Cowan

Morton Cowan, UCSF

Morton described how the gold standard treatment for SCID, which is hematopoietic or blood stem cell transplantation, is only safe and effective when the patient has an HLA matched sibling donor. Unfortunately, many patients don’t have this option and face life-threatening challenges of transplant rejection (graft-versus host disease). To combat this issue, Morton and his team are using gene therapy to genetically correct the blood stem cells of SCID patients and transplant those cells back into these patients so that they can generate healthy immune cells.

They are currently developing a gene therapy for a particularly hard-to-treat form of SCID that involves deficiency in a protein called Artemis, which is essential for the development of the immune system and for repairing DNA damage in cells. Currently his group is conducting the necessary preclinical work to start a gene therapy clinical trial for children with Artemis-SCID.

Treating spinal cord injury in the clinic

Casey Case, Asterias Biotherapeutics

Casey Case, Asterias Biotherapeutics

Casey Case, Senior VP of Research and Nonclinical Development at Asterias Biotherapeutics, gave an update on the CIRM-funded clinical trial for cervical (neck) spinal cord injury (SCI). They are currently testing the safety of transplanting different doses of their oligodendrocyte progenitor cells (AST-OPC1) in a group of SCI patients. The endpoint for this trial is an improvement in movement greater than two motor levels, which would offer a significant improvement in a patient’s ability to do some things on their own and reduce the cost of their healthcare. You can read more about these results and the ongoing study in our recent blogs (here, here).

Opinion: Scientists should be patient advocates

David Higgins gave the most moving speech of the day. He is a Parkinson’s patient and the Patient Advocate on the CIRM board and he spoke about what patient advocates are and how to become one. David explained how, these days, drug development and patient advocacy is more patient oriented and patients are involved at the center of every decision whether it be questions related to how a drug is developed, what side effects should be tolerated, or what risks are worth taking. He also encouraged the Bridges students to become patient advocates and understand what their needs are by asking them.

David Higgins, Parkinson's advocate and CIRM Board member

David Higgins

“As a scientist or clinician, you need to be an ambassador. You have a job of translating science, which is a foreign language to most people, and you can all effectively communicate to a lay audience without being condescending. It’s important to understand what patients’ needs are, and you’ll only know that if you ask them. Patients have amazing insights into what needs to be done to develop new treatments.”

Bridging the gap between research and patients

The Bridges conference is still ongoing with more poster presentations, a career panel, and scientific talks on discovery and translational stem cell research and commercializing stem cell therapies to all patients in need. It truly is a once in a lifetime opportunity for the Bridges students, many of whom are considering careers in science and regenerative medicine and are taking advantage of the opportunity to talk and network with prominent scientists.

If you’re interested in hearing more about the Bridges conference, follow us on twitter (@CIRMnews, @DrKarenRing, #CIRMBridges2016) and on Instagram (@CIRM_Stemcells).

T cell fate and future immunotherapies rely on a tag team of genetic switches

Imagine if scientists could build microscopic smart missiles that specifically seek out and destroy deadly, hard-to-treat cancer cells in a patient’s body? Well, you don’t have to imagine it actually. With techniques such as chimeric antigen receptor (CAR) T therapy, a patient’s own T cells – immune system cells that fight off viruses and cancer cells – can be genetically modified to produce customized cell surface proteins to recognize and kill the specific cancer cells eluding the patient’s natural defenses. It is one of the most exciting and promising techniques currently in development for the treatment of cancer.

Human T Cell (Wikipedia)

Human T Cell (Wikipedia)

Although there have been several clinical trial success stories, it’s still early days for engineered T cell immunotherapies and much more work is needed to fine tune the approach as well as overcome potential dangerous side effects. Taking a step back and gaining a deeper understanding of how stem cells specialize into T cells in the first place could go a long way into increasing the efficiency and precision of this therapeutic strategy.

Enter the CIRM-funded work of Hao Yuan Kueh and others in Ellen Rothenberg’s lab at CalTech. Reporting yesterday in Nature Immunology, the Rothenberg team uncovered a time dependent array of genetic switches – some with an ON/OFF function, others with “volume” control – that together control the commitment of stem cells to become T cells.

Previous studies have shown that the protein encoded by the Bcl11b gene is the key master switch that when activated sets a “no going back” path toward a T cell fate. A group of other genes, including Runx1, TCF-1 and GATA-3 are known to play a role in activating Bcl11b. The dominant school of thought is that these proteins gradually accumulate at the Bcl11b gene and once a threshold level is achieved, the proteins combine to enable the Bcl11b activation switch to flip on. However, other studies suggest that some of these proteins may act as “pioneer” factors that loosen up the DNA structure and allow the other proteins to readily access and turn on the Bcl11b gene. Figuring out which mechanism is at play is critical to precisely manipulating T cell development through genetic engineering.

To tease out the answer, the CalTech team engineered mice such that cells with activated Bcl11b would glow which allows visualizing the fate of single cells. We reached out to Dr. Kueh on the rationale for this experimental approach:

Hao Yuan Kueh, CalTech

Hao Yuan Kueh, CalTech

“To fully understand how genes are controlled, we need to watch them turn on and off in single, living cells over time.  As cells in our body are unique and different from one another, standard measurement methods, which average over millions of cells, often do not tell us the entire picture.”

The team examined the impact of inhibiting the T cell specific proteins GATA-3 and TCF-1 at different stages in T cell development in single cells. When the production of these two proteins were blocked in very early T cell progenitor (ETPs) cells, activation of Bcl11b was dramatically reduced. But that’s not what they observed when the experiment was repeated in a later stage of T cell development. In this case, blocking GATA-3 and TCF-1 had a much weaker impact on Bcl11b. So GATA-3 and TCF-1 are important for turning on Bcl11b early in T cell development but are not necessary for maintaining Bcl11b activation at later stages.

Inhibition of Runx1, on the other hand, did lead to a reduction in Bcl11b in these later T cell development stages. Making Runx1 levels artificially high conversely led to elevated Bcl11b in these cells.

Together, these results point to GATA-3 and TCF-1 as the key factors for turning on Bcl11b to commit cells to a T cell fate and then they hand off their duties to Runx1 to keep Bcl11b on and maintaining the T cell identity. Dr. Kuhn sums up the results and their implications this way:

“Our work shows that control of gene expression is very much a team effort, where some proteins flip the gene’s master ON-OFF switch, and others set its expression levels after it turns on…These results will help us generate customized T-cells to fight cancer and other diseases.  As T-cells are specialized to recognize and fight foreign agents in our body, this therapy strategy holds much promise for diseases that are difficult to treat with standard drug-based methods.  Also, these intricate gene regulation mechanisms are likely to be in play in other cell types in our body, not just T-cells, and so we believe our results will be widely relevant.”

UCSF study explains how chronic inflammation impairs blood stem cell function

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Inflammation is the immune system’s natural protective response to infection and injury. It involves the activation and mobilization of immune cells that can kill off foreign invaders and help repair damaged tissue. At the heart of the inflammatory response are hematopoietic stem cells (HSCs). These are blood stem cells found in the bone marrow that give rise to all blood cell types.

Under normal conditions, HSCs lie in a dormant state. But in response to inflammation they are triggered to rapidly divide and to differentiate into the immune cells needed. This initial response is beneficial in fighting off infection, however if left on for too long, HSCs lose their ability to self-renew (or make more of themselves) and regenerate a healthy blood system.

IL-1: Good Cop or Bad Cop?

A key player in the immune response to inflammation is a cytokine protein called Interleukin-1 or IL-1. It plays a beneficial role during an initial or acute inflammatory response: IL-1 along with other pro-inflammatory cytokines signals to HSCs that inflammation or infection is occurring and recruits certain immune cells from the blood into the tissue where they are needed.

However, IL-1 can also have negative effects on the immune system and high levels of this cytokine are found in patients with chronic inflammatory diseases such as obesity, diabetes and atherosclerosis. When HSCs are exposed IL-1 for long periods of time, they lose their regenerative abilities and  overproduce specific types of aggressive immune cells called myeloid cells that are needed to fight infection and repair injury but can also cause chronic inflammation and tissue damage. This can create an imbalance of blood cell types that impairs the function of the immune system.

So is IL-1 the good cop or the bad cop when it comes to inflammation and disease? A new CIRM-funded study from the University of California San Francisco (UCSF), published yesterday in Nature Cell Biology, might have the answer.

A double-edged sword

The study was led by first author Dr. Eric Pietras, who is now an Assistant Professor of Hematology at the University of Colorado Anschutz Medical Campus. He along with senior author and UCSF Professor Dr. Emmanuelle Passegue, were interested in understanding whether IL-1 was a bystander or an active player in causing this transformation in HSCs that leads to chronic inflammatory disease.

To answer this question, Pietras and Passegue exposed mouse HSCs to IL-1, both in a cell culture dish and in mice. They found that IL-1 drove HSCs to rapidly differentiate into myeloid cells by activating a molecular circuit directed by the PU.1 gene, which is important for regulating HSC blood production. However, when mice were exposed to IL-1 for an extended period of 70 days – to mimic chronic inflammation – their HSCs were no longer able to do their normal job of regenerating all the cells of the blood and immune system.

I reached out to Dr. Pietras and asked him to explain what new insights his study has produced about the role of IL-1 during inflammation.

Eric Pietras

Eric Pietras

“IL-1 really is a double-edged sword; it’s great for turning on HSCs when you need them to make new first-responder myeloid cells quickly due to an injury or infection, and on the other hand, failure to turn the signal back off severely disrupts the ability of HSCs to make a balanced, healthy blood system, particularly in a regenerative context. I think this provides us with a clearer picture of why the blood system often functions poorly in chronic inflammatory disease patients.”

 

Negative effects of IL-1 are reversible

There’s good news though. Pietras and his team were able to reverse the negative effects of chronic IL-1 exposure on HSCs by simply removing IL-1. They proved this by transplanting HSCs from mice that were chronically treated with IL-1 and then taken off the treatment for a few weeks into irradiated mice that had no bone marrow and therefore no immune system. The transplanted HSCs were able to repopulate the entire immune system of the irradiated mice and did not show any regenerative dysfunction due to previous IL-1 treatment.

Dr. Pietras commented on the importance of their study:

“An important dimension of our study is to show in principle that HSCs can recover their functionality and return to making a healthy and balanced blood system if you can give them a break from the constant presence of inflammatory signals. This tells us that the negative effects of chronic inflammation on HSCs can be largely reversed if you can provide them with a break from the constant ‘emergency’ state IL-1 makes them think they’re in. This could impact how we treat chronic inflammatory disease.

 

Blocking IL-1 to treat chronic inflammation

So will drugs that inhibit IL-1 be a future therapy for patients suffering from chronic inflammatory disease? Anti-IL-1 drugs have been around for a while – one example is Kineret, which is an FDA-approved treatment for rheumatoid arthritis. But there are many other diseases caused by chronic inflammation that may or may not benefit from such treatment.

Dr. Passegue, in a UCSF press release, explained that their study’s findings are important for determining how anti-IL-1 therapy could be beneficial for patients.

“Understanding this mechanism helps us understand why these drugs are such promising treatments for patients with chronic inflammation.”

She also hinted that IL-1 could be a double-edged sword in stem cell populations of other tissues and that “reducing chronic IL-1 exposure may be an important approach for improving stem cell health and tissue function in the context of both inflammatory disease and normal aging.”


Related Links:

Scientists tackle aging by stabilizing defective blood stem cells in mice

Aging is an inevitable process that effects every cell, tissue, and organ in your body. You can live longer by maintaining a healthy, active lifestyle, but there is no magic pill that can prevent your body’s natural processes from slowly breaking down and becoming less efficient. As author Chinua Achebe would say, “Things Fall Apart”.

Adult stem cells are an unfortunate victim of the aging process. They have the important job of replenishing the cells in your body throughout your lifetime. However, as you grow older, adult stem cells lose their regenerative ability and fail to maintain the integrity and function of their tissues and organs. This can happen for a number of reasons, but no matter the cause, dysfunctional stem cells can accelerate aging and contribute to a shortened lifespan.

So to put it simply, aging adult stem cells = decline in stem cell function = shortened lifespan.

Dysfunctional blood stem cells make an unhappy immune system

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

A good example of this process is hematopoietic stem cells (HSCs), which are adult stem cells found in bone marrow that make all the cells in our blood and immune system. When HSCs get old, they lose their edge and fail to generate some of the important blood cell types that are crucial for a healthy immune system. This can be life-threatening for elderly people who are at higher risk for infections and disease.

So how can we improve the function of aging HSCs to boost the immune system in older people and potentially extend their healthy years of life? A team of researchers from Germany might have an answer. They’ve identified a genetic switch that revitalizes aged, defective HSCs in mice and prolongs their lifespan. They published their findings this week in Nature Cell Biology.

Identifying the Per-petrator for aging HSCs

The perpetrator in this story is a gene called Per2. The team identified Per2 through a genetic screen of hundreds of potential tumor suppressor genes that could potentially impair the regenerative abilities of HSCs in response to DNA damage caused by aging.

It turns out that the Per2 gene is turned on in a subset of HSCs, called lymphoid-HSCs, that preferentially generate blood cells in the lymphatic system. These include B and T cells, both important parts of our immune system. When Per2 is turned on in lymphoid-HSCs, it activates the DNA damage response pathway. While responding to DNA damage may sound like a good thing, it also slows down the cell division process and prevents lymphoid-HSCs from producing their normal amount of lymphoid cells. Adding insult to injury, Per2 also activates the p53-dependent apoptosis pathway, which causes programmed cell death and further reduces the number of HSCs in reserve.

To address these problems, the team decided to delete the Per2 gene in mice and study the function of their HSCs as they aged. They found that removing Per2 stabilized lymphoid-HSCs and rescued their ability to generate the appropriate number of lymphoid cells. Per2 deletion also boosted their immune system, making the mice less susceptible to infection, and extended their lifespan by as much as 15 percent.

A key finding was that deleting Per2 did not increase the incidence of tumors in the aging mice – a logical concern as Per2 mutations in humans are link to increased cancer risk.

Per2 might not be a Per-fect solution for healthy aging

In summary, getting rid of Per2 in the HSCs of older mice improves their function and the function of their immune system while also extending their lifespan.

Senior author on the study, Karl Lenhard Rudolph, commented about their findings in a news release:

Karl Lenhard Rudolph. Photo: Anne Günther/FSU

Karl Lenhard Rudolph.

“All in all, these results are very promising, but equally surprising. We did not expect such a strong connection between switching off a single gene and improving the immune system so clearly.”

 

 

So Per2 may be a good healthy aging target in mice, but the real question is whether these results will translate to humans. Per2 is a circadian rhythm gene and is important for regulating the sleep-wake cycle. Deleting this gene in humans could cause sleep disorders and other unwanted side effects.

Rudolph acknowledges that his team needs to move their focus from mouse to humans.

“It is not yet clear whether this mutation in humans would have a benefit such as improved immune functions in aging — it is of great interest for us to further investigate this question.”