Stem Cell Stories that Caught Our Eye: GPS for Skin & Different Therapies for Aging vs. Injured Muscles?

Skin stem cells specialize into new skin by sensing neighborhood crowding
When embarking on a road trip, the GPS technology inside our smartphones helps us know where we are and how to get where we’re going. The stem cells buried in the deepest layers of our skin don’t have a GPS and yet, they do just fine determining their location, finding their correct destination and becoming the appropriate type of skin cell. And as a single organ, all the skin covering your body maintains the right density and just the right balance of skin stem cells versus mature skin cells as we grow from a newborn into adult.

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Skin cells growing in a petri dish (green: cytoskeleton, red: cell-cell junction protein).
Credit: MPI for Biology of Aging

This easily overlooked but amazing feat is accomplished as skin cells are continually born and die about every 30 days over your lifetime. How does this happen? It’s an important question to answer considering the skin is our first line of defense against germs, toxins and other harmful substances.

This week, researchers at the Max Planck Institute for Biology of Aging in Cologne, Germany reported a new insight into this poorly understood topic. The team showed that it all comes down to the skin cells sensing the level of crowding in their local environment. As skin stem cells divide, it puts the squeeze on neighboring stem cells. This physical change in tension on these cells “next door” triggers signals that cause them to move upward toward the skin surface and to begin maturing into skin cells.

Lead author Yekaterina Miroshnikova explained in a press release the beauty of this mechanism:

“The fact that cells sense what their neighbors are doing and do the exact opposite provides a very efficient and simple way to maintain tissue size, architecture and function.”

The research was picked up by Phys.Org on Tuesday and was published in Nature Cell Biology.

Stem cells respond differently to aging vs. injured muscle
From aging skin, we now move on to our aging and injured muscles, two topics I know oh too well as a late-to-the-game runner. Researchers at the Sanford Burnham Prebys Medical Discovery Institute (SBP) in La Jolla report a surprising discovery that muscle stem cells respond differently to aging versus injury. This important new insight could help guide future therapeutic strategies for repairing muscle injuries or disorders.

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Muscle stem cell (pink with green outline) sits along a muscle fiber.
Image: Michael Rudnicki/OIRM

Muscle stem cells, also called satellite cells, make a small, dormant population of cells in muscle tissue that springs to life when muscle is in need of repair. It turns out that these stem cells are not identical clones of each other but instead are a diverse pool of cells.  To understand how the assortment of muscle stem cells might respond differently to the normal wear and tear of aging, versus damage due to injury or disease, the research team used a technology that tracks the fate of individual muscle stem cells within living mice.

The analysis showed a clear but unexpected result. In aging muscle, the muscle stem cells maintained their diversity but their ability to divide and grow declined. However, the opposite result was observed in injured muscle: the muscle stem cell diversity became limited but the capacity to divide was not affected. In a press release, team leader Alessandra Sacco explains the implications of these findings for therapy development:

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Alessandra Sacco, PhD

“This study has shown clear-cut differences in the dynamics of muscle stem cell pools during the aging process compared to a sudden injury. This means that there probably isn’t a ‘one size fits all’ approach to prevent the decline of muscle stem cells. Therapeutic strategies to maintain muscle mass and strength in seniors will most likely need to differ from those for patients with degenerative diseases.”

This report was picked up yesterday by Eureka Alert and published in Cell Stem Cell.

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jCyte Shares Encouraging Update on Clinical Trial for Retinitis Pigmentosa

Stepping out of the darkness into light. That’s how patients are describing their experience after participating in a CIRM-funded clinical trial targeting a rare form of vision loss called retinitis pigmentosa (RP). jCyte, the company conducting the trial, announced 12 month results for its candidate stem cell-based treatment for RP.

RP is a genetic disorder that affects approximately 1 in 40,000 individuals and 1.5 million people globally. It causes the destruction of the light-sensing cells at the back of the eye called photoreceptors. Patients experience symptoms of vision loss starting in their teenage years and eventually become legally blind by middle age. While there is no cure for RP, there is hope that stem cell-based therapies could slow its progression in patients.

Photoreceptors look healthy in a normal retina (left). Cells are damaged in the retina of an RP patient (right). (Source National Eye Institute)

jCyte is one of the leaders in developing cell-based therapies for RP. The company, which was founded by UC Irvine scientists led by Dr. Henry Klassen, is testing a product called jCell, which is composed of pluripotent stem cell-derived progenitor cells that develop into photoreceptors. When transplanted into the back of the eye, they are believed to release growth factors that prevent further damage to the surviving cells in the retina. They also can integrate into the patient’s retina and develop into new photoreceptor cells to improve a patient’s vision.

Positive Results

At the Annual Ophthalmology Innovation Summit in November, jCyte announced results from its Phase 1/2a trial, which was a 12-month study testing two different doses of transplanted cells in 28 patients. The company reported a “favorable safety profile and indications of potential benefit” to patient vision.

The patients received a single injection of cells in their worst eye and their visual acuity (how well they can see) was then compared between the treated and untreated eye. Patients who received the lower dose of 0.5 million cells were able to see one extra letter on an eye chart with their treated eye compared to their untreated eye while patients that received the larger dose of 3 million cells were able to read 9 more letters. Importantly, none of the patients experienced any significant side effects from the treatment.

According to the company’s news release, “patient feedback was particularly encouraging. Many reported improved vision, including increased sensitivity to light, improved color discrimination and reading ability and better mobility. In addition, 22 of the 28 patients have been treated in their other eye as part of a follow-on extension study.”

One of these patients is Rosie Barrero. She spoke to us earlier this year about how the jCyte trial has not only improved her vision but has also given her hope. You can watch her video below.

Next Steps

These results suggest that the jCell therapy is safe (at least at the one year mark) to use in patients and that larger doses of jCell are more effective at improving vision in patients. jCyte CEO, Paul Bresge commented on the trial’s positive results:

Paul Bresge

“We are very encouraged by these results. Currently, there are no effective therapies to offer patients with RP. We are moving forward as quickly as possible to remedy that. The feedback we’ve received from trial participants has been remarkable. We look forward to moving through the regulatory process and bringing this easily-administered potential therapy to patients worldwide.”

Bresge and his company will be able to navigate jCell through the regulatory process more smoothly with the product’s recent Regenerative Medicine Advanced Therapy (RMAT) designation from the US Food and Drug Administration (FDA). The FDA grants RMAT to regenerative medicine therapies for serious diseases that have shown promise in early-stage clinical trials. The designation allows therapies to receive expedited review as they navigate their way towards commercialization.

jCyte is now evaluating the safety and efficacy of jCell in a Phase2b trial in a larger group of up to 85 patients. CIRM is also funding this trial and you can read more about it on our website.


Related Links:

 

A new study suggests CRISPR gene editing therapies should be customized for each patient

You know a scientific advance is a big deal when it becomes the main premise and title of a Jennifer Lopez-produced TV drama. That’s the case for CRISPR, a revolutionary gene-editing technology that promises to yield treatments for a wide range of genetic diseases.

In fact, clinical trials using the CRISPR method are already underway with more on the horizon. And at CIRM, we’re funding several CRISPR projects including a candidate gene and stem cell therapy that applies CRISPR to repair a genetic mutation found in sickle cell anemia patients.

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Animation by Todd Dubnicoff/CIRM

While these projects are moving full steam ahead, a study published this week in PNAS suggests a note of caution. They report that the natural genetic variability that is found when comparing  the DNA sequences of individuals has the potential to negatively impact the effectiveness of a CRISPR-based treatment and in some cases, could lead to dangerous side effects. As a result, the research team – a collaboration between Boston Children’s Hospital and the University of Montreal – recommends that therapy products using CRISPR should be customized to take into account the genetic variation between patients.

CRISPR 101
While other gene-editing methods pre-date CRISPR, the gene-editing technique has taken the research community by storm because of its ease of use. Pretty much any lab can incorporate it into their studies. CRISPR protein can cut specific DNA sequence within a person’s cells with the help of an attached piece of RNA. It’s pretty straight-forward to customize this “guide” RNA molecule so that it recognizes a desired DNA sequence that is in need of repair or modification.

https://player.vimeo.com/video/112757040

Because CRISPR activity heavily relies on the guide RNA molecule’s binding to a specific DNA sequence, there have been on-going concerns that a patient’s genetic variability could hamper the effectiveness of a given CRISPR therapy if it didn’t bind well. Even worse, if the genetic variability caused the CRISPR product to bind and inactivate a different region of DNA, say a gene responsible for suppressing cancer growth, it could lead to dangerous, so-called off target effects.

Although, studies have been carried out to measure the frequency of these potential CRISPR mismatches, many of the analyses depend on a reference DNA sequence from one individual. But as senior author Stuart Orkin, of Dana-Farber Boston Children’s Cancer and Blood Disorders Center, points out in a press release, this is not an ideal way to gauge CRISPR effectiveness and safety:

orkin

Stuart Orkin

“Humans vary in their DNA sequences, and what is taken as the ‘normal’ DNA sequence for reference cannot account for all these differences.”

 

 

One DNA sequence is not like the other
So, in this study, the research team analyzed previously published DNA sequence data from 7,444 people. And they focused on 30 disease genes that various researchers were targeting with CRISPR gene-editing. The team also generated 3,000 different guide RNAs with which to target those 30 disease genes.

The analysis showed that, in fact, about 50 percent of the guide RNAs could potentially have mismatches due to genetic variability found in these patients’ DNA sequences. These mismatches could lead to less effective binding of CRISPR to the disease gene target, which would reduce the effectiveness of the gene editing. And, though rare, the team also found cases in which an individual’s genetic variability could cause the CRISPR guide RNA to bind and cut in the wrong spot.

Matthew Canver, an MD-PhD student at Harvard Medical School who is also an author in the study, points out these less-than-ideal activities could also impact other gene editing techniques. Canver gives an overall recommendation how to best move forward with CRISPR-based therapy development:

canver, matthew

Matthew Canver

“The unifying theme is that all these technologies rely on identifying stretches of DNA bases very specifically. As these gene-editing therapies continue to develop and start to approach the clinic, it’s important to make sure each therapy is going to be tailored to the patient that’s going to be treated.”

 

Using the AIDS virus to help children battling a deadly immune disorder

Ronnie Kashyap, patient in SCID clinical trial: Photo Pawash Priyank

More than 35 million people around the world have been killed by HIV, the virus that causes AIDS. So, it’s hard to think that the same approach the virus uses to infect cells could also be used to help children battling a deadly immune system disorder. But that’s precisely what researchers at UC San Francisco and St. Jude Children’s Research Hospital are doing.

The disease the researchers are tackling is a form of severe combined immunodeficiency (SCID). It’s also known as ‘bubble baby’ disease because children are born without a functioning immune system and in the past were protected from germs within the sterile environment of a plastic bubble. Children with this disease often die of infections, even from a common cold, in the first two years of life.

The therapy involves taking the patient’s own blood stem cells from their bone marrow, then genetically modifying them to correct the genetic mutation that causes SCID. The patient is then given low-doses of chemotherapy to create space in their bone marrow for the news cells. The gene-corrected stem cells are then transplanted back into the infant, creating a new blood supply and a repaired immune system.

Unique delivery system

The novel part of this approach is that the researchers are using an inactivated form of HIV as a means to deliver the correct gene into the patient’s cells. It’s well known that HIV is perfectly equipped to infiltrate cells, so by taking an inactivated form – meaning it cannot infect the individual with HIV – they are able to use that infiltrating ability for good.

The results were announced at the American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta.

The researchers say seven infants treated and followed for up to 12 months, have all produced the three major immune system cell types affected by SCID. In a news release, lead author Ewelina Mamcarz, said all the babies appear to be doing very well:

“It is very exciting that we observed restoration of all three very important cell types in the immune system. This is something that’s never been done in infants and a huge advantage over prior trials. The initial results also suggest our approach is fundamentally safer than previous attempts.”

One of the infants taking part in the trial is Ronnie Kashyap. We posted a video of his story on our blog, The Stem Cellar.

If the stem cell-gene therapy combination continues to show it is both safe and effective it would be a big step forward in treating SCID. Right now, the best treatment is a bone marrow transplant, but only around 20 percent of infants with SCID have a sibling or other donor who is a good match. The other 80 percent have to rely on a less well-matched bone marrow transplant – usually from a parent – that can still leave the child prone to life-threatening infections or potentially fatal complications such as graft-versus-host disease.

CIRM is funding two other clinical trials targeting SCID. You can read about them here and here.

Scientists find switch that targets immunotherapies to solid tumors

Cancer immunotherapies harness the power of the patient’s own immune system to fight cancer. One type of immunotherapy, called adoptive T cell therapy, uses immune cells called CD8+ Killer T cells to target and destroy tumors. These T cells are made in the spleen and lymph nodes and they can migrate to different locations in the body through a part of our circulatory system known as the lymphatic system.

CD8+ T cells can also leave the circulation and travel into the body’s tissues to fight infection and cancer. Scientists from the Scripps Research Institute and UC San Diego are interested in learning how these killer T cells do just that in hopes of developing better immunotherapies that can specifically target solid tumors.

In a study published last week in the journal Nature, the teams discovered that a gene called Runx3 acts as a switch that programs CD8+ T cells to set up shop within tissues outside of the circulatory system, giving them access to solid tumors.

“Runx3 works on chromosomes inside killer T cells to program genes in a way that enables the T cells to accumulate in a solid tumor,” said Matthew Pipkin, co-senior author and Associate Professor at The Scripps Research Institute.

Study authors Adam Getzler, Dapeng Wang and Matthew Pipkin of The Scripps Research Institute collaborated with scientists at the University of California, San Diego.

They discovered Runx3 by comparing what genes were expressed in CD8+ T cells found in the lymphatic system to CD8+ T cells that were found in tissues outside of the circulation. They then screened thousands of potential factors for their ability to influence CD8+ T cells to infiltrate solid tumors.

“We found a distinct pattern,” Pipkin said. “The screens showed that Runx3 is one at the top of a list of regulators essential for T cells to reside in non-lymphoid tissues.”

The team then set out to prove that Runx3 was a key factor in getting CD8+ T cells to localize at the site of solid tumors. To do this, they took T cells that either overexpressed Runx3 or did not express Runx3 in these cells. The T cells were then transplanted into mice with melanoma through a process known as adoptive cell transfer. Overexpression of Runx3 in T cells not only reduced tumor size but also extended lifespan in the mice. On the other hand, removing Runx3 expression had a negative impact on their survival rate.

This research, which was supported in part by CIRM funding, offers a new strategy for developing better cancer immunotherapies for solid tumors.

Pipkin concluded in a Scripps Research Institutes News Release,

“Knowing that modulating Runx3 activity in T cells influences their ability to reside in solid tumors opens new opportunities for improving cancer immunotherapy. We could probably use Runx3 to reprogram adoptively transferred cells to help drive them to amass in solid tumors.”

CIRM interviews Lorenz Studer: 2017 recipient of the Ogawa-Yamanaka Stem Cell Prize [Video]

For eight long years, researchers who were trying to develop a stem cell-based therapy for Parkinson’s disease – an incurable movement disorder marked by uncontrollable shaking, body stiffness and difficulty walking – found themselves lost in the proverbial wilderness. In initial studies, rodent stem cells were successfully coaxed to specialize into dopamine-producing nerve cells, the type that are lost in Parkinson’s disease. And further animal studies showed these cells could treat Parkinson’s like symptoms when transplanted into the brain.

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studer-lorenz

Lorenz Studer, MD
Photo Credit: Sloan Kettering

But when identical recipes were used to make human stem cell-derived dopamine nerve cells the same animal experiments didn’t work. By examining the normal developmental biology of dopamine neurons much more closely, Lorenz Studer cracked the case in 2011. Now seven years later, Dr. Studer, director of the Center for Stem Cell Biology at the Memorial-Sloan Kettering Cancer Center, and his team are on the verge of beginning clinical trials to test their Parkinson’s cell therapy in patients

It’s for these bottleneck-busting contributions to the stem cell field that Dr. Studer was awarded the Gladstone Institutes’ 2017 Ogawa-Yamanaka Stem Cell Prize. Now in its third year, the prize was founded by philanthropists Hiro and Betty Ogawa along with  Shinya Yamanaka, Gladstone researcher and director of the Center for iPS Cell Research and Application at Kyoto University, and is meant to inspire and celebrate discoveries that build upon Yamanaka’s Nobel prize winning discovery of induced pluripotent stem cells (iPSCs).

LorenzStuder_OgawaAward2017-12

(L to R) Shinya Yamanaka, Andrew Ogawa, Deepak Srivastava present Lorenz Studer the 2017 Ogawa-Yamanaka Stem Cell Prize at Gladstone Institutes. Photo Credit: Todd Dubnicoff/CIRM

Studer was honored at the Gladstone in November and presented the Ogawa-Yamanka Stem Cell Prize Lecture. He was kind enough to sit down with me for a brief video interview (watch it below) a few minutes before he took the stage. He touched upon his Parkinson’s disease research as well as newer work related to hirschsprung disease, a dangerous intestinal disorder often diagnosed at birth that is caused by the loss of nerve cells in the gut. Using human embryonic stem cells and iPSCs derived from hirschsprung patients, Studer’s team has worked out the methods for making the gut nerve cells that are lost in the disease. This accomplishment has allowed his lab to better understand the disease and to make solid progress toward a stem cell-based therapy.

His groundbreaking work has also opened up the gates for other Parkinson’s researchers to make important insights in the field. In fact, CIRM is funding several interesting early stage projects aimed at moving therapy development forward:

We posted the 8-minute video with Dr. Studer today on our official YouTube channel, CIRM TV. You can watch the video here:

And for a more detailed description of Studer’s research, watch Gladstone’s webcast recording of his entire lecture:

CIRM-Funded Research Makes Multiple Headlines this Week

When it rains it pours.

This week, multiple CIRM-funded studies appeared in the news, highlighting the exciting progress our Agency is making towards funding innovative stem cell research and promoting the development of promising stem cell therapies for patients.

Below are highlights.


Fate Therapeutics Partners with UC San Diego to Develop Cancer Immunotherapy

Last week, Dr. Dan Kaufman and his team at UC San Diego, received a $5.15 million therapeutic translational research award from CIRM to advance the clinical development of a stem cell-derived immunotherapy for acute myelogenous leukemia (AML), a rare form of blood cancer.

Today, it was announced that the UCSD team is entering into a research collaboration with a San Diego biopharmaceutical company Fate Therapeutics to develop a related immunotherapy for blood cancers. The therapy consists of immune cells called chimeric antigen receptor-targeted natural killer (CAR NK) cells that can target tumor cells and stop their growth. Fate Therapeutics has developed an induced pluripotent stem cell (iPSC) platform to develop and optimize CAR NK cell therapies targeting various cancers.

According to an article by GenBio, this new partnership is already bearing fruit.

“In preclinical studies using an ovarian cancer xenograft model, Dr. Kaufman and Fate Therapeutics had shown that a single dose of CAR-targeted NK cells derived from iPSCs engineered with the CAR construct significantly inhibited tumor growth and increased survival compared to NK cells containing a CAR construct commonly used for T-cell immunotherapy.”

 


City of Hope Brain Cancer Trial Featured as a Key Trial to Watch in 2018

Xconomy posted a series this week forecasting Key Clinical Data to look out for next year. Today’s part two of the series mentioned a recent CIRM-funded trial for glioblastoma, an aggressive, deadly brain cancer.

Christine Brown and her team at the City of Hope are developing a CAR-T cell therapy that programs a patient’s own immune cells to specifically target and kill cancer cells, including cancer stem cells, in the brain. You can read more about this therapy and the Phase 1 trial on our website.

Alex Lash, Xconomy’s National Biotech Editor, argued that good results for this trial would be a “huge step forward for CAR-T”.

Alex Lash

“While CAR-T has proven its mettle in certain blood cancers, one of the biggest medical questions in biotech is whether the killer cells can also eat up solid tumors, which make up the majority of cancer cases. Glioblastoma—an aggressive and usually incurable brain cancer—is a doozy of a solid tumor.”


ViaCyte Receives Innovative New Product Award for Type 1 Diabetes

Last week, San Diego-based ViaCyte was awarded the “Most Innovative New Product Award” by CONNECT, a start-up accelerator focused on innovation, for its PEC-Direct product candidate. The product is a cell-based therapy that’s currently being tested in a CIRM-funded clinical trial for patients with high-risk type 1 diabetes.

In a company news release published today, ViaCyte’s CEO Paul Laikind commented on what the award signifies,

Paul Laikind

“This award acknowledges how ViaCyte has continually broken new ground in stem cell research, medical device engineering, and cell therapy scaling and manufacturing. With breakthrough technology, clinical stage product candidates, an extensive intellectual property estate, and a strong and dedicated team, ViaCyte has all the pieces to advance a transformative new life-saving approach that could help hundreds of thousands of people with high-risk type 1 diabetes around the world.”

Comparing two cellular reprogramming methods from one donor’s cells yields good news for iPSCs

In 2012, a mere six years after his discovery of induced pluripotent stem cells (iPSCs), Shinya Yamanaka was awarded the Nobel Prize in Medicine. Many Nobel winners aren’t recognized until decades after their initial groundbreaking studies. That goes to show you the importance of Yamanaka’s technique, which can reprogram a person’s cells, for example skin or blood, into embryonic stem cell-like iPSCs by just adding a small set of reprogramming factors.

These iPSCs are pluripotent, meaning they can be specialized, or differentiated, into virtually any cell type in the body. With these cells in hand, researchers have a powerful tool to study human disease and to develop treatments using human cells directly from patients. And at the same time, this cell source helps avoid the ethical concerns related to embryonic stem cells.

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Induced pluripotent stem cell (iPSC) colonies.
Image Credit: Joseph Wu

Still, there has been lingering uneasiness about how well iPSCs match up to embryonic stem cells (ESCs), considered the gold-standard of pluripotent stem cells. One source of those concerns is that the iPSC method doesn’t completely reprogram cells and they retain memory of their original cell source, in the form of chemical – also called epigenetic – modifications of the cells’ DNA structure. So, if a researcher were to make, say, heart muscle cells from iPSCs that have an epigenetic memory of its skin cell origins, any resulting conclusions about a given disease study or cell therapy could be less accurate than ESC-related results. But a report published yesterday in PNAS should help relieve these worries.

The CIRM-funded study – a collaboration between the labs of Joseph Wu and Michael Synder at Stanford University and Shoukhrat Mitalipov at Oregon Health & Science University – carried out an exhaustive series of experiments that carefully compared the gene activity and cell functions of iPSC-derived cells with cells derived from embryonic stem cells. The teams sought to compare cells generated from the same person to be sure any differences were not the result of genetics. To make this “apples-to-apples” comparison, they generated embryonic stem cells using another reprogramming technique called somatic cell nuclear transfer (SCNT).

With SCNT, a nucleus from an adult cell is transferred to an egg which has its own nucleus removed. The resulting cell becomes reprogrammed back into an embryo from which embryonic stem cells are generated – the researchers call them NT-ESCs for short. In this study, the skin cell sample used for making the iPSCs and the cell nucleus used for making the NT-ESCs came from the same person. In scientific lingo, the iPSCs and SCNT stem cells are considered isogenic.

Now, it turns out the NT-ESC reprogramming process is more complete and eliminates epigenetic memory of the original cell source. So why even bother with iPSCs if you have NT-ESCs? There are big disadvantages with SCNT: it’s a complex technique – only a limited number of labs pull it off – and it requires donated human eggs which carries ethical issues. So, if a direct comparison iPSCs and SNCT stem cells shows little difference then it would be fair to argue that iPSCs can replace NT-ESCs for deriving patient-specific stem cells.

And that’s exactly what the teams found, as Dr. Wu summarized it to me in an interview:

“Direct comparison between differentiated cells derived from iPSCs and SCNT had never been performed because it had been difficult to generate patient-specific ESCs by the SCNT method. Collaborating with Dr. Shoukhrat Mitalipov at Oregon Health & Science University and Dr. Michael Snyder at Stanford University, we compared patient-specific cardiomocytes (heart muscle cells) and endothelial (blood vessel) cells derived by these two reprogramming methods (SCNT and iPSCs) and found they were relatively equivalent regarding molecular and functional features.”

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Blood vessel cells derived by iPSC (left) and SCNT (right) reprogramming methods.
Image credit: Joseph Wu

Because the heart muscle and blood vessel cells were similar regardless of reprogramming method, it suggests that the epigenetic memory that remained in the iPSCs is less of a worry. Dr. Wu explained to me this way:

joewu

Joseph Wu

“If iPSCs carry substantial epigenetic memory of the cell-of-origin, it is unlikely these iPSCs can differentiate to a functional cardiac cell or blood vessel cell. Only the stem cells free of significant epigenetic memory can differentiate into functional cells.”

 

Hopefully these results hold up over time because it will bode well for the countless iPSC-related disease studies as well as the growing number of iPSC-related projects that are nearing clinical trials.

Hey, what’s the big idea? CIRM Board is putting up more than $16.4 million to find out

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David Higgins, CIRM Board member and Patient Advocate for Parkinson’s disease; Photo courtesy San Diego Union Tribune

When you have a life-changing, life-threatening disease, medical research never moves as quickly as you want to find a new treatment. Sometimes, as in the case of Parkinson’s disease, it doesn’t seem to move at all.

At our Board meeting last week David Higgins, our Board member and Patient Advocate for Parkinson’s disease, made that point as he championed one project that is taking a new approach to finding treatments for the condition. As he said in a news release:

“I’m a fourth generation Parkinson’s patient and I’m taking the same medicines that my grandmother took. They work but not for everyone and not for long. People with Parkinson’s need new treatment options and we need them now. That’s why this project is worth supporting. It has the potential to identify some promising candidates that might one day lead to new treatments.”

The project is from Zenobia Therapeutics. They were awarded $150,000 as part of our Discovery Inception program, which targets great new ideas that could have a big impact on the field of stem cell research but need some funding to help test those ideas and see if they work.

Zenobia’s idea is to generate induced pluripotent stem cells (iPSCs) that have been turned into dopaminergic neurons – the kind of brain cell that is dysfunctional in Parkinson’s disease. These iPSCs will then be used to screen hundreds of different compounds to see if any hold potential as a therapy for Parkinson’s disease. Being able to test compounds against real human brain cells, as opposed to animal models, could increase the odds of finding something effective.

Discovering a new way

The Zenobia project was one of 14 programs approved for the Discovery Inception award. You can see the others on our news release. They cover a broad array of ideas targeting a wide range of diseases from generating human airway stem cells for new approaches to respiratory disease treatments, to developing a novel drug that targets cancer stem cells.

Dr. Maria Millan, CIRM’s President and CEO, said the Stem Cell Agency supports this kind of work because we never know where the next great idea is going to come from:

“This research is critically important in advancing our knowledge of stem cells and are the foundation for future therapeutic candidates and treatments. Exploring and testing new ideas increases the chances of finding treatments for patients with unmet medical needs. Without CIRM’s support many of these projects might never get off the ground. That’s why our ability to fund research, particularly at the earliest stage, is so important to the field as a whole.”

The CIRM Board also agreed to invest $13.4 million in three projects at the Translation stage. These are programs that have shown promise in early stage research and need funding to do the work to advance to the next level of development.

  • $5.56 million to Anthony Oro at Stanford to test a stem cell therapy to help people with a form of Epidermolysis bullosa, a painful, blistering skin disease that leaves patients with wounds that won’t heal.
  • $5.15 million to Dan Kaufman at UC San Diego to produce natural killer (NK) cells from embryonic stem cells and see if they can help people with acute myelogenous leukemia (AML) who are not responding to treatment.
  • $2.7 million to Catriona Jamieson at UC San Diego to test a novel therapeutic approach targeting cancer stem cells in AML. These cells are believed to be the cause of the high relapse rate in AML and other cancers.

At CIRM we are trying to create a pipeline of projects, ones that hold out the promise of one day being able to help patients in need. That’s why we fund research from the earliest Discovery level, through Translation and ultimately, we hope into clinical trials.

The writer Victor Hugo once said:

“There is one thing stronger than all the armies in the world, and that is an idea whose time has come.”

We are in the business of finding those ideas whose time has come, and then doing all we can to help them get there.

 

 

 

Stem Cell Stories That Caught our Eye: Stem Cell Therapies for Stroke and Duchenne Muscular Dystrophy Patients

With the Thanksgiving holiday behind us, we’re back to the grind at CIRM. Here are two exciting CIRM-funded stem cell stories that happened while you were away.

Stanford Scientists Are Treating Stroke Patients with Stem Cells

Smithsonian Magazine featured the work of a CIRM-funded scientist in their December Magazine issue. The article, “A Neurosurgeon’s Remarkable Plan to Treat Stroke Victims with Stem Cells”, features Dr. Gary Steinberg, who is the Chair of Neurosurgery at Stanford Medical Center and the founder of the Stanford Stroke Center.

Gary Steinberg (Photo by Jonathan Sprague)

The brain and its 100 billion cells need blood, which carries oxygen and nutrients, to function. When that blood supply is cut off, brain cells start to die and patients experience a stroke. Stroke can happen in one of two ways: either by blood clots that block the arteries and blood vessels that send blood to the brain or by blood vessels that burst within the brain itself. Symptoms experienced by stroke victims vary based on the severity of the stroke, but often patients report experiencing numbness or paralysis in their limbs or face, difficulty walking, talking and understanding.

Steinberg and his team at Stanford are developing a stem cell treatment to help stroke patients. Steinberg believes that not all brain cells die during a stroke, but rather some brain cells become “dormant” and stop functioning instead. By transplanting stem cells derived from donated bone marrow into the brains of stroke patients, Steinberg thinks he can wake up these dormant cells much like how the prince wakens Sleeping Beauty from her century of enchanted sleep.

Basically, the transplanted cells act like a defibrillator for the dormant cells in the stroke-damaged area of the brain. Steinberg thinks that the transplanted cells secrete proteins that signal dormant brain cells to wake up and start functioning normally again, and that they also trigger a “helpful immune response” that prompts the brain to repair itself.

Sonia has seen first hand how a stroke can rob you of even your most basic abilities.

Steinberg tested this stem cell treatment in a small clinical trial back in 2013. 18 patients were treated and many of them showed improvements in their symptoms. The Smithsonian piece mentions a particular patient who had a remarkable response to the treatment. Sonia Olea Coontz, at age 32, suffered a stroke that robbed her of most of her speech and her ability to use her right arm and leg. After receiving Steinberg’s stem cell treatment, Sonia rapidly improved and was able to raise her arm above her head and gained most of her speech back. You can read more about her experience in our Stories of Hope.

In collaboration with a company called SanBio, Steinberg’s team is now testing this stem cell therapy in 156 stroke patients in a CIRM-funded phase 2 clinical trial. The trial will help answer the question of whether this treatment is safe and also effective in a larger group of patients.

The Smithsonian article, which I highly recommend reading, shared Steinberg’s future aspirations to pursue stem cell therapies for traumatic brain and spinal cord injuries as well as neurodegenerative diseases like Alzheimer’s, Parkinson’s and ALS.

 

Capricor Approved to Launch New Clinical Trial for Duchenne Muscular Dystrophy

On Wednesday, Capricor Therapeutics achieved an exciting milestone for its leading candidate CAP-1002 – a stem cell-based therapy developed to treat boys and young men with a muscle-wasting disease called Duchenne muscular dystrophy (DMD).

The Los Angeles-based company announced that it received approval from the US Food and Drug Administration (FDA) for their investigational new drug (IND) application to launch a new clinical trial called HOPE II that’s testing repeated doses of CAP-1002 cells in DMD patients. The cells are derived from donated heart tissue and are believed to release regenerative factors that strengthen heart and other muscle function in DMD patients.

Capricor is currently conducting a Phase 2 trial, called HOPE-1, that’s testing a single dose of CAP-1002 cells in 24 DMD patients. CIRM is funding this trial and you can learn more about it on our clinical dashboard website and watch a video interview we did with a young man who participated in the trial.

Earlier this year, the company shared encouraging, positive results from the HOPE-1 trial suggesting that the therapy was improving some heart function and upper limb movement six months after treatment and was well-tolerated in patients. The goal of the new trial will be to determine whether giving patients repeated doses of the cell therapy over time will extend the benefits in upper limb movement in DMD patients.

In a news release, Capricor President and CEO Dr. Linda Marbán shared her company’s excitement for the launch of their new trial and what this treatment could mean for DMD patients,

Linda Marban, CEO of Capricor Therapeutics

“The FDA’s clearance of this IND upon its initial submission is a significant step forward in our development of CAP-1002. While there are many clinical initiatives in Duchenne muscular dystrophy, this is one of the very few to focus on non-ambulant patients. These boys and young men are looking to maintain what function they have in their arms and hands and, based on our previous study, we think CAP-1002 may be able to do exactly that.”