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

Deleting a single gene can boost blood stem cell regeneration

A serious side effect that cancer patients undergoing chemotherapy experience is myelosuppression. That’s a big word for a process that involves the decreased production of the body’s immune cells from hematopoietic stem cells (HSCs) or blood stem cells in the bone marrow. Without these important cells that make up the immune system, patients are at risk for major infections and even death.

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.

Scientists are trying to find ways to treat cancer patients that have undergone myelosuppressive therapies, as well as patients that need bone marrow transplants to replace their own bone marrow that’s been damaged or removed. One possible solution is boosting the regenerative capacity of HSCs. Transplanting HSCs that are specially primed to reproduce rapidly into cells of the immune system could improve the outcome of bone marrow transplants in patients.

Deleting Grb10 boost blood stem cell regeneration

A CIRM-funded team from the UCLA Broad Stem Cell Institute and the Jonsson Comprehensive Cancer Center has identified a single gene that can be manipulated to boost HSC regeneration in mice. The study, which was published in Cell Reports, found that deleting or turning off expression of an imprinted gene called Grb10 in HSCs caused these blood stem cells to reproduce more robustly after being transplanted into mice that had their bone marrow removed.

I just used another big word in that last paragraph, so let me explain. An imprinted gene is a gene that is expressed or activated based on which parent it was inherited from. Typically, you receive one copy of a gene from your mother and one from your father and both are expressed – a process called Mendelian inheritance. But imprinted genes are different – they are marked with specific epigenetic tags that silence their expression in the sperm or egg cells of the parents. Thus if you inherited an imprinted gene from your mother, the other copy of that gene from your father would be expressed and vice versa.

Scientists have discovered that imprinted genes are important for human development and also for directing what cell types adult stem cells like HSCs develop into. The team from UCLA led by senior author Dr. John Chute, was interested in answering a different question: are imprinted genes involved in determining the function of HSCs? They compared two different populations of HSCs derived from mouse bone marrow: a normal, healthy population and HSCs exposed to total body irradiation (TBI), which destroys the immune system. They discovered that the expression of an imprinted gene called Grb10 was dramatically higher in HSCs exposed to TBI compared to healthy HSCs.

Cell Reports

Deleting Grb10  increases blood stem cell regeneration in the bone marrow of irradiated mice (bottom) compared to normal mice (top). Cell Reports

Because Grb10 is an imprinted gene, the scientists deleted either the paternal or maternal copy of that gene in mice. While deleting the paternal Grb10 gene had no effect on the function of HSCs, maternal deletion dramatically boosted the capacity of HSCs to divide and make more copies of themselves. Without the maternal copy of Grb10, HSCs were able to regenerate at a much faster scale than normal HSCs.

To further prove their point, the team transplanted normal HSCs and HSCs that lacked Grb10 into TBI or fully irradiated mice. HSCs that lacked Grb10 were able to regenerate themselves and produce other immune cells more robustly 20 weeks after transplantation compared to normal HSCs.

Potential applications and future studies

This study offers two important findings. First, they discovered that Grb10 plays an important role “in regulating HSC self-renewal following transplantation and HSC regeneration in response to injury.” Second, they found that inhibiting Grb10 function in HSCs could have potential therapeutic applications for boosting “hematopoietic regeneration in the setting of HSC transplantation or following myelosuppressive injury.” Patients in need of bone marrow transplants could potentially receive more benefit from transplants of HSCs that don’t express the Grb10 gene.

In my opinion, further studies should be done to further understand the role of Grb10 in regulating HSC self-renewal and regeneration. What is the benefit of having this gene expressed in HSCs if inhibiting its expression leads to an increased regenerative capacity? Is it to prevent cancer from forming? Additionally, the authors will need to address the potential long-term side effects of inhibiting Grb10 expression in HSCs. They did report that mice that lacked the Grb10 gene did not develop blood cancers at one year of age which is good news. They also suggested that instead of deleting Grb10, new drugs could be identified that inhibit Grb10 function in HSCs.

Accelerating the drive for new stem cell treatments

Acceleration

Acceleration is defined as the “increase in the rate or speed of something.” For us that “something” is new stem cell treatments for patients with unmet medical needs. Today our governing Board just approved a $15 million partnership with Quintiles to help us achieve that acceleration.

Quintiles was awarded the funding to create a new Accelerating Center. The goal of the center is to give stem cell researchers the support they need to help make their clinical trials successful.

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

randy-at-podium1CIRM President Randy Mills addresses the CIRM Board

“Many scientists are brilliant researchers but have little experience or expertise in running a clinical trial; this Accelerating Center means they don’t have to develop those skills; we provide them for them. This partnership with Quintiles means that scientists don’t have to learn how to manage patient enrollment or how to create a data base to manage the results. Instead they are free to focus on what they do best, namely science.”

How does it work? Well, if a researcher has a promising therapy and approval from the US Food and Drug Administration (FDA) to start a clinical trial, the Accelerating Center helps them get that trial off the ground. It helps them find the patients they need, get those patients consented and ready for the trial, and then helps manage the trial and the data from the trial.

The devil is in the details

Managing those details can be a key factor in determining whether a clinical trial is going to be successful. Last year, a study in the New England Journal of Medicine listed the main reasons why clinical trials fail.

Among the reasons are:

  • Poor study design: Selecting the wrong patients, the wrong dosing and the wrong endpoint, as well as bad data and bad site management cause severe problems.
  • Poor management: A project manager who does not have enough experience in costing and conducting clinical trials will lead to weak planning, with no clear and real timelines, and to ultimate failure.

We hope our partnership with Quintiles in this Accelerating Center will help researchers avoid those and the other pitfalls. As the world’s largest provider of biopharmaceutical development and commercial outsourcing services, Quintiles has a lot of experience and expertise in this area. On its Twitter page it’s slogan is “Better, smarter, faster trials” so I think we made a smart choice.

When Randy Mills first pitched this idea to the Board, he said that he is a great believer in “not asking fish to learn how to fly, they should just do what they do best”.

The Accelerating Center means scientists can do what they do best, and we hope that leads to what patients need most; treatments and cures.


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Family ties help drive UCLA’s search for a stem cell treatment for Duchenne muscular dystrophy

Duchenne

April Pyle, Courtney Young and Melissa Spencer: Photo courtesy UCLA Broad Stem Cell Research Center

People get into science for all sorts of different reasons. For Courtney Young the reason was easy; she has a cousin with Duchenne muscular dystrophy.

Now her work as part of a team at UCLA has led to a new approach that could eventually help many of those suffering from Duchenne, the most common fatal childhood genetic disease.

The disease, which usually affects boys, leads to progressive muscle weakness, which means children may lose their ability to walk by age 12 and eventually results in breathing difficulties and heart disease.

Duchenne is caused by a defective gene, which leads to very low levels of a protein called dystrophin – an important element in building strong, healthy muscles. There are many sections of the gene where this defect or mutation can be found, but in 60 percent of cases it occurs within one particular hot spot of DNA. That’s the area that the UCLA team focused on, helped in part by a grant from CIRM.

Skin in the game

First they obtained skin cells from people with Duchenne muscular dystrophy and turned those into iPS cells. Those cells have the ability to become any other cell in the body and, just as importantly for this research, still retain the genetic code from the person they came from. In this case it meant they still had the genetic defect that led to Duchenne muscular dystrophy.

Then the researchers used a gene editing tool called CRISPR (we’ve written about this a lot in the past, you can a couple of those articles  here and here  and here)  to remove the genetic mutations that cause Duchenne. They then turned those iPS cells into skeletal muscle cells and transplanted them into mice that had the genetic mutation that meant they couldn’t produce dystrophin.

To their delight they found that the transplanted cells produced dystrophin in the mice.

Breaking new ground

April Pyle, a co-senior author of the study, which appears in the journal Cell Stem Cell,  said, in a news release, this was the first study to use human iPS cells to correct the problem in muscle tissue caused by Duchenne:

“This work demonstrates the feasibility of using a single gene editing platform, plus the regenerative power of stem cells to correct genetic mutations and restore dystrophin production for 60 percent of Duchenne patients.”

The researchers say this is an important step towards developing a new treatment for Duchenne muscular dystrophy, but caution there are still many years of work before this approach will be ready to test in people.

For Courtney Young advancing the science is not just professionally gratifying, it’s also personally satisfying:

“I already knew I was interested in science, so after my cousin’s diagnosis, I decided to dedicate my career to finding a cure for Duchenne. It makes everything a lot more meaningful, knowing that I’m doing something to help all the boys who will come after my cousin. I feel like I’m contributing and I’m excited because the field of Duchenne research is advancing in a really positive direction.”