The Story of a South African Bubble Boy and a Gene Therapy That Gave Him His Life Back

Ayaan Isaacs, health24

Ayaan Isaacs was born in South Africa on March 4th, 2016 as a seemingly healthy baby. But only a few days in to life, he contracted a life-threatening liver infection. He thankfully survived, only to have the doctors discover a few weeks later that he had something much more troubling – a rare disease that left him without a functioning immune system.

Ayaan was diagnosed with X-linked severe combined immunodeficiency (SCID), which is often referred to as ‘bubble baby’ disease because patients are extremely susceptible to infection and must live in sterile environments. SCID patients can be cured with a blood stem cell transplant if they have a genetically matched donor. Unfortunately for Ayaan, only a partially matched donor was available, which doesn’t guarantee a positive outcome.

Ayaan’s parents were desperate for an alternative treatment to save Ayaan’s life. It was at this point that they learned about a clinical trial at St. Jude Children’s Research hospital in Memphis, Tennessee. The trial is treating SCID patients with a stem cell gene therapy that aims to give them a new functioning immune system. The therapy involves extracting the patient’s blood-forming stem cells and genetically correcting the mutation that causes SCID. The corrected blood stem cells are then transplanted back into the patient where they rebuild a healthy immune system.

Ayaan was able to enroll in the trial, and he was the first child in Africa to receive this life-saving gene therapy treatment. Ayaan’s journey with bubble boy disease was featured by South Africa’s health24 earlier this year. In the article, his mom Shamma Sheik talked about the hope that this gene therapy treatment brought to their family.

“No child should have to die just because they are unable to find a donor. Gene therapy offered Ayaan a chance at life that he ordinarily would not have had. I was fortunate to have found an alternative therapy that is working and already showing remarkable results. We are mindful that this is still an experimental treatment and there are complications that can arise; however, I am very optimistic that he will return to South Africa with a functioning immune system.”

Carte Blanche, an investigative journalism program in South Africa, did a feature video of Ayaan in February. Although the video is no longer available on their website, it did reveal that four months after Ayaan’s treatment, his condition started to improve suggesting that the treatment was potentially working.

We’ve written previously about another young boy named Ronnie who was diagnosed with X-linked SCID days after he was born. Ronnie also received the St. Jude stem cell gene therapy in a CIRM-funded clinical trial at the UCSF Benioff Children’s Hospital. Ronnie was treated when he was six months old and just celebrated his first birthday as a healthy, vibrant kid thanks to this trial. You can hear more about Ronnie’s moving story from his dad, Pawash Priyank, in the video below.

Our hope is that powerful stories like Ayaan’s and Ronnie’s will raise awareness about SCID and the promising potential of stem cell gene therapies to cure patients of this life-threatening immune disease.

Ronnie and his parents celebrating his 1st birthday. (Photo courtesy of Pawash Priyank)


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Stem Cell Agency’s Diane Winokur hailed as Visionary

Diane and JT

CIRM Board member Diane Winokur with CIRM Board Chair Jonathan Thomas at FFB Awards dinner

Generally speaking, I am not a huge fan of gala dinners. It’s not that I don’t like seeing people who do remarkable things getting a well-deserved honor. It’s just that the dinners often go on too long and the food is usually not very good (hey, this is San Francisco, those things matter). But last night’s Foundation Fighting Blindness Visionary Awards in San Francisco was definitely an exception to that rule.

Academy of Sciences Grand Opening

Academy of Sciences in San Francisco

Now it may be that the awards were held in the spectacular Academy of Sciences building in Golden Gate Park, or that the food was delicious. But I think the real reason is that CIRM Board member Diane Winokur was one of those being honored. The other honoree was Dr. Jacque Duncan, an amazing physician at UC San Francisco who has dedicated her life to battling diseases of the retina. The whole event was deeply emotional, and truly inspiring.

Now, Diane is a remarkable woman in many respects. She’s the Board’s Patient Advocate member for ALS (better known as Lou Gehrig’s disease) and multiple sclerosis. But Diane also considers herself a Patient Advocate for all Californians and works hard to help advance the research that could help them. She has a personal connection to vision loss as well; one of her dear friends has lost his sight because of retinitis pigmentosa, and his daughter is losing hers because of the same disease.

Diane at podiumDiane highlighted the work that CIRM is doing to help battle vision destroying diseases; how we have invested more than $125 million in 25 different projects. She talked about the encouraging news from clinical trials we are funding targeting retinitis pigmentosa and dry age-related macular degeneration. Diane said:

“These stem cell clinical trials show that progress is being made. Not as fast as we would like, but as everyone here knows, good science takes time. As a patient advocate on the CIRM Board it’s my role to represent the patient, to be their voice in making decisions about what projects to fund.

Patients are at the heart of everything we do at CIRM, from deciding on funding issues to supporting clinical trials. That’s why I feel so honored to get this award. It comes from an organization, that is equally committed to doing all it can to help people in need, to putting the patient at the center of everything they do.”

It’s clear that patients really are at the heart of the work the Foundation Fighting Blindness (FFB) does. As the organizations CEO Benjamin Yerxa said:

“We support 77 labs in the US, often funding projects no one else would. We do this because we know it is necessary to advance the field. And we are going to keep doing this as best we can, as fast as we can, for as long as we can, because we know so many people are depending on us to help them.”

The other honoree, Jacque Duncan, said after attending many previous Visionary Award dinners and seeing the people being honored it was humbling to be in that company. She talked about the exciting progress being made in the field and the people who are making it possible.

“None of this happens by chance. The path to developing new treatments takes the passion of scientists and doctors, and the commitment of patients to raising the funds needed to do this research. One gala dinner at a time, one Vision Walk at a time. All of this creates community and a common purpose. I truly believe that because of this, tomorrow will be brighter than today.”

Perhaps it’s only appropriate to leave the last word to Diane, who ended her speech saying:

“The Nobel prize winning physicist Heinrich Rohrer once said that science means constantly walking a tightrope between blind faith and curiosity; between expertise and creativity; between bias and openness; between experience and epiphany; in short, between an old today and a new tomorrow.

I believe that working together, CIRM and the Foundation Fighting Blindness, we can create that new tomorrow.”

New Insights into Adult Neurogenesis

To be a successful scientist, you have to expect the unexpected. No biological process or disease mechanism is ever that simple when you peel off its outer layers. Overtime, results that prove a long-believed theory can be overturned by new results that suggest an alternate theory.

UCSF scientist Arturo Alvarez-Buylla is well versed with the concept of unexpected results. His lab’s research is focused on understanding adult neurogenesis – the process of creating new nerve cells (called neurons) from neural stem cells (NSCs).

For a long time, the field of adult neurogenesis has settled on the theory that brain stem cells divide asymmetrically to create two different types of cells: neurons and neural stem cells. In this way, brain stem cells populate the brain with new neurons and they also self-renew to maintain a constant stem cell supply throughout the adult animal’s life.

New Insights into Adult Neurogenesis

Last week, Alvarez-Buylla and his colleagues published new insights on adult neurogenesis in mice in the journal Cell Stem Cell. The study overturns the original theory of asymmetrical neural stem cell division and suggests that neural stem cells divide in a symmetrical fashion that could eventually deplete their stem cell population over the lifetime of the animal.

Arturo Alvarez-Buylla explained the study’s findings in an email interview with the Stem Cellar:

Arturo Alvarez-Bulla

“Our results are not what we expected. Our work shows that postnatal NSCs are not being constantly renewed by splitting them asymmetrically, with one cell remaining as a stem cell and the other as a differentiated cell. Instead, self-renewal and differentiation are decoupled and achieved by symmetric divisions.”

In brief, the study found that neural stem cells (called B1 cells) divide symmetrically in an area of the adult mouse brain called the ventricular-subventricular zone (V-SVZ). Between 70%-80% of those symmetric divisions produced neurons while only 20%-30% created new B1 stem cells. Alvarez-Buylla said that this process would result in the gradual depletion of B1 stem cells over time and seems to be carefully choreographed for the length of the lifespan of a mouse.

What does this mean?

I asked Alvarez-Buylla how his findings in mice will impact the field and whether he expects human adult neurogenesis to follow a similar process. He explained,

“The implications are quite wide, as it changes the way we think about neural stem cell retention and aging. The cells do not seem open ended with unlimited potential to be renewed, which results in a progressive decrease in NSC number and neurogenesis with time.  Understanding the mechanisms regulating proliferation of NSCs and their self-renewal also provides new insights into how the whole process of neurogenesis is choreographed over long periods by suggesting that differentiation (generation of neurons) is regulated separately from renewal.”

He further explained that mice generate new neurons in the V-SVZ brain region throughout their lifetime while humans only appear to generate new neurons during infancy in the equivalent region of the human brain called the SVZ. In humans, he said, it remains unclear where and how many neural stem cells are retained after birth.

I also asked him how these findings will impact the development of neural stem cell-based therapies for neurological or neurodegenerative diseases. Alvarez-Buylla shared interesting insights:

“Our data also indicate that upon a self-renewing division, sibling NSCs may not be equal to each other. While one NSC might stay quiescent [non-dividing] for an extended period of time, its sister cell might become activated earlier on and either undergo another round of self-renewal or differentiate. Thus, for cell-replacement therapies it will be important to understand which kind of neuron the NSC of interest can produce, and when. The use of NSCs for brain repair requires a detailed understanding of which NSC subset will be utilized for treatment and how to induce them to produce progeny. The study also suggests that factors that control NSC renewal may be separate from those that control generation of neurons.”

Scientists developing adult NSC-based therapies will definitely need to take note of Alvarez-Buylla’s findings as some NSC populations might be more successful therapeutically than others.

Neural Stem Cells in the Wild

I’ll conclude with a beautiful image that the study’s first author, Kirsten Obernier, shared with me. It’s shows the V-SVZ of the mouse brain and a neural stem cell in red making contact with a blood vessel in green and neurons in blue.

Image of the mouse brain with a neural stem cell in red. (Credit: Kirsten Obernier, UCSF)

Kirsten described the complex morphology of B1 NSCs in the mouse brain and their dynamic behavior, which Kirsten observed by taking a time lapsed video of NSCs dividing in the mouse V-SVZ. Obernier and Alvarez-Buylla hypothesize that these NSCs could be receiving signals from their surrounding environment that tell them whether to make neurons or to self-renew.

Clearly, further research is necessary to peel back the complex layers of adult neurogenesis. If NSC differentiation is regulated separately from self-renewal, their insights could shed new light on how conditions of unregulated self-renewal like brain tumors develop.

Progress to a Cure for Bubble Baby Disease

Welcome back to our “Throwback Thursday” series on the Stem Cellar. Over the years, we’ve accumulated an arsenal of exciting stem cell stories about advances towards stem cell-based cures for serious diseases. Today we’re featuring stories about the progress of CIRM-funded clinical trials for the treatment of a devastating, usually fatal, primary immune disease that strikes newborn babies.

evangelina in a bubble

Evie, a former “bubble baby” enjoying life by playing inside a giant plastic bubble

‘Bubble baby disease’ will one day be a thing of the past. That’s a bold statement, but I say it with confidence because of the recent advancements in stem cell gene therapies that are curing infants of this life-threatening immune disease.

The scientific name for ‘bubble baby disease’ is severe combined immunodeficiency (SCID). It prevents the proper development of important immune cells called B and T cells, leaving newborns without a functioning immune system. Because of this, SCID babies are highly susceptible to deadly infections, and without treatment, most of these babies do not live past their first year. Even a simple cold virus can be fatal.

Scientists are working hard to develop stem cell-based gene therapies that will cure SCID babies in their first months of life before they succumb to infections. The technology involves taking blood stem cells from a patient’s bone marrow and genetically correcting the SCID mutation in the DNA of these cells. The corrected stem cells are then transplanted back into the patient where they can grow and regenerate a healthy immune system. Early-stage clinical trials testing these stem cell gene therapies are showing very encouraging results. We’ll share a few of these stories with you below.

CIRM-funded trials for SCID

CIRM is funding three clinical trials, one from UCLA, one at Stanford and one from UCSF & St. Jude Children’s Research Hospital, that are treating different forms of SCID using stem cell gene therapies.

Adenosine Deaminase-Deficient SCID

The first trial is targeting a form of the disease called adenosine deaminase-deficient SCID or ADA-SCID. Patients with ADA-SCID are unable to make an enzyme that is essential for the function of infection-fighting immune cells called lymphocytes. Without working lymphocytes, infants eventually are diagnosed with SCID at 6 months. ADA-SCID occurs in approximately 1 in 200,000 newborns and makes up 15% of SCID cases.

CIRM is funding a Phase 2 trial for ADA-SCID that is testing a stem cell gene therapy called OTL-101 developed by Dr. Don Kohn and his team at UCLA and a company called Orchard Therapeutics. 10 patients were treated in the trial, and amazingly, nine of these patients were cured of their disease. The 10th patient was a teenager who received the treatment knowing that it might not work as it does in infants. You can read more about this trial in our blog from earlier this year.

In a recent news release, Orchard Therapeutics announced that the US Food and Drug Administration (FDA) has awarded Rare Pediatric Disease Designation to OTL-101, meaning that the company will qualify for priority review for drug approval by the FDA. You can read more about what this designation means in this blog.

X-linked SCID

The second SCID trial CIRM is funding is treating patients with X-linked SCID. These patients have a genetic mutation on a gene located on the X-chromosome that causes the disease. Because of this, the disease usually affects boys who have inherited the mutation from their mothers. X-linked SCID is the most common form of SCID and appears in 1 in 60,000 infants.

UCSF and St. Jude Children’s Research Hospital are conducting a Phase 1/2 trial for X-linked SCID. The trial, led by Dr. Brian Sorrentino, is transplanting a patient’s own genetically modified blood stem cells back into their body to give them a healthy new immune system. Patients do receive chemotherapy to remove their diseased bone marrow, but doctors at UCSF are optimizing low doses of chemotherapy for each patient to minimize any long-term effects. According to a UCSF news release, the trial is planning to treat 15 children over the next five years. Some of these patients have already been treated and we will likely get updates on their progress next year.

CIRM is also funding a third clinical trial out of Stanford University that is hoping to make bone marrow transplants safer for X-linked SCID patients. The team, led by Dr. Judy Shizuru, is developing a therapy that will remove unhealthy blood stem cells from SCID patients to improve the survival and engraftment of healthy bone marrow transplants. You can read more about this trial on our clinical trials page.

SCID Patients Cured by Stem Cells

These clinical trial results are definitely exciting, but what is more exciting are the patient stories that we have to share. We’ve spoken with a few of the families whose children participated in the UCLA and UCSF/St. Jude trials, and we asked them to share their stories so that other families can know that there is hope. They are truly inspiring stories of heartbreak and joyful celebration.

Evie is a now six-year-old girl who was diagnosed with ADA-SCID when she was just a few months old. She is now cured thanks to Don Kohn and the UCLA trial. Her mom gave a very moving presentation about Evie’s journey at the CIRM Bridges Trainee Annual Meeting this past July.  You can watch the 20-minute talk below:

Ronnie’s story

Ronnie SCID kid

Ronnie: Photo courtesy Pawash Priyank

Ronnie, who is still less than a year old, was diagnosed with X-linked SCID just days after he was born. Luckily doctors told his parents about the UCSF/St. Jude trial and Ronnie was given the life-saving stem cell gene therapy before he was six months old. Now Ronnie is building a healthy immune system and is doing well back at home with his family. Ronnie’s dad Pawash shared his families moving story at our September Board meeting and you can watch it here.

Our mission at CIRM is to accelerate stem cell treatments to patients with unmet medical needs. We hope that by funding promising clinical trials like the ones mentioned in this blog, that one day soon there will be approved stem cell therapies for patients with SCID and other life-threatening diseases.

Using stem cells to take an inside approach to fixing damaged livers

Often on the Stem Cellar we write about work that is in a clinical trial. But getting research to that stage takes years and years of dedicated work. Over the next few months we are going to profile some of the scientists we fund who are doing Discovery, or early stage research, to highlight the importance of this work in developing the treatments that could ultimately save lives.

 This first profile is by Pat Olson, Ph.D., CIRM’s Vice President of Discovery & Translation

liver

Most of us take our liver for granted.  We don’t think about the fact that our liver carries out more than 500 functions in our bodies such as modifying and removing toxins, contributing to digestion and energy production, and making substances that help our blood to clot.  Without a liver we probably wouldn’t live more than a few days.

Our liver typically functions well but certain toxins, viral infections, long-term excess alcohol consumption and metabolic diseases such as obesity and type 2 diabetes can have devastating effects on it.  Under these conditions, functional liver cells, called hepatocytes, die and are replaced with cells called myofibroblasts.  Myofibroblasts are cells that secrete excess collagen leading to fibrosis, a form of scarring, throughout the liver.  Eventually, a liver transplant is required but the number of donor livers available for transplant is small and the number of persons needing a functional liver is large.  Every year in the United States,  around 6,000 patients receive a new liver and more than 35,000 patients die of liver disease.

Searching for options

willenbring photo

Dr. Holger Willenbring

Dr. Holger Willenbring, a physician scientist at UCSF, is one of the CIRM-funded researchers pursuing a stem cell/regenerative medicine approach to discover a treatment for patients with severe liver disease.  There are significant challenges to treating liver disease including getting fully multi-functional hepatocytes and getting them to engraft and/or grow sufficiently to achieve adequate mass for necessary liver functions.

In previous CIRM–funded discovery research, Dr. Willenbring and his team showed that they could partially reprogram human fibroblasts (the most common cell found in connective tissue) and then turn them into immature hepatocytes.  (see our Spotlight on Liver Disease video from 2012 featuring Dr. Willenbring.) These immature hepatocytes, when transplanted into an immune-deficient mouse model of human liver failure, were shown to mature over time into hepatocytes that were comparable to normal human hepatocytes both in their gene expression and their function.

This was an important finding in that it suggested that the liver environment in a living animal (in vivo), rather than in a test tube (in vitro) in the laboratory, is important for full multi-functional maturation of hepatocytes.  The study also showed that these transplanted immature human hepatocytes could proliferate and improve the survival of this mouse model of chronic human liver disease.  But, even though this model was designed to emphasizes the growth of functional human hepatocytes, the number of cells generated was not great enough to suggest that transplantation could be avoided

A new approach

Dr. Willenbring and his team are now taking the novel approach of direct reprogramming inside the mouse.  With this approach, he seeks to avoid the challenge of low engraftment and proliferation of transplanted hepatocytes generated in the lab and transplanted. Instead, they aim to take advantage of the large number of myofibroblasts in the patient’s scarred liver by turning them directly into hepatocytes.

Recently, he and his team have shown proof-of principle that they can deliver genes to myofibroblasts and turn them into hepatocytes in a mouse. In addition these in vivo myofibroblasts-derived hepatocytes are multi-functional, and can multiply in number, and can even reverse fibrosis in a mouse with liver fibrosis.

From mice to men (women too)

Our latest round of funding for Dr. Willenbring has the goal of moving and extending these studies into human cells by improving the specificity and effectiveness of reprogramming of human myofibroblasts into hepatocytes inside the animal, rather than the lab.

He and his team will then conduct studies to test the therapeutic effectiveness and initial safety of this approach in preclinical models. The ultimate goal is to generate a potential therapy that could eventually provide hope for the 35,000 patients who die of liver disease each year in the US.

 

 

CIRM Board Appoints Dr. Maria Millan as President and CEO

Dr. Maria Millan, President and CEO of CIRM, at the September Board meeting. (Todd Dubnicoff, CIRM)

Yesterday was a big day for CIRM. Our governing Board convened for its September ICOC meeting and appointed Dr. Maria Millan as our new President and CEO. Dr. Millan has been serving as the Interim President/CEO since July, replacing former President Dr. Randal Mills.

Dr. Millan has been at CIRM since 2012 and was instrumental in the development of CIRM’s infrastructure programs including the Alpha Stem Cell Clinics Network and the agency’s Strategic Plan, a five-year plan that lays out our agency’s goals through 2020. Previously, Dr. Millan was the Vice President of Therapeutics at CIRM, helping the agency fund 23 new clinical trials since the beginning of 2016.

The Board vote to appoint Dr. Millan as President and CEO was unanimous and enthusiastic. Chairman of the Board, Jonathan Thomas, shared the Board’s sentiments when he said,

“Dr. Millan is absolutely the right person for this position. Having seen Dr. Millan as the Interim CEO of CIRM for three months and how she has operated in that position, I am even more enthusiastic than I was before. I am grateful that we have someone of Maria’s caliber to lead our Agency.”

Dr. Millan has pursued a career devoted to helping patients. Before working at CIRM, she was an organ transplant surgeon and researcher and served as an Associate Professor of Surgery and Director of the Pediatric Organ Transplant Program at Stanford University. Dr. Millan was also the Vice President and Chief Medical Officer at StemCells, Inc.

In her permanent role as President, Dr. Millan is determined to keep CIRM on track to achieve the goals outlined in our strategic plan and to achieve its mission to accelerate treatments to patients with unmet needs. She commented in a CIRM press release,

“I joined the CIRM team because I wanted to make a difference in the lives of patients. They are the reason why CIRM exists and why we fund stem cell research. I am humbled and very honored to be CIRM’s President and look forward to further implementing our agency’s Strategic Plan in the coming years.”

The Board also voted to fund two new Alpha Stem Cell Clinics at UC Davis and UC San Francisco and five new clinical trials. Three of the clinical awards went to projects targeting cancer.

The City of Hope received $12.8 million to fund a Phase 1 trial targeting malignant gliomas (an aggressive brain cancer) using CAR-T cell therapy. Forty Seven Inc. received $5 million for a Phase 1b clinical trial treating acute myeloid leukemia. And Nohla Therapeutics received $6.9 million for a Phase 2 trial testing a hematopoietic stem cell and progenitor cell therapy to help patients suffering from neutropenia, a condition that leaves people susceptible to deadly infections, after receiving chemotherapy for acute myeloid leukemia.

The other two trials target diabetes and end stage kidney failure. ViaCyte, Inc. was awarded $20 million to fund a Phase 1/2 clinical trial to test its PEC-Direct islet cell replacement therapy for high-risk type 1 diabetes. Humacyte Inc. received $14.1 million to fund a Phase 3 trial that is comparing the performance of its acellular bioengineered vessel with the current standard of dialysis treatment for kidney disease patients.

The Board also awarded $5.2 million to Stanford Medicine for a late stage preclinical project that will use CRISPR gene editing technology to correct the sickle cell disease mutation in blood-forming stem cells to treat patients with sickle cell disease. This award was particularly well timed as September is Sickle Cell Awareness month.

The Stanford team, led by Dr. Matthew Porteus, hopes to complete the final experiments required for them to file an Investigational New Drug (IND) application with the FDA so they can be approved to start a clinical trial hopefully sometime in 2018. You can read more about Dr. Porteus’ work here and you can read our past blogs featuring Sickle Cell Awareness here and here.

With the Board’s vote yesterday, CIRM’s clinical trial count rises to 40 funded trials since its inception. 23 of these trials were funded after the launch of our Strategic Plan bringing us close to the half way point of funding 50 new clinical trials by 2020. With more “shots-on-goal” CIRM hopes to increase the chances that one of these trials will lead to an FDA-approved therapy for patients.


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Stem Cell Stories that caught our eye: a womb with a view, reversing aging and stabilizing stem cells

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.

Today we bring you a trifecta of stem cell stories that were partially funded by grants from CIRM.

A womb with a view: using 3D imaging to observe embryo implantation. Scientists have a good understanding of how the beginning stages of pregnancy happen. An egg cell from a woman is fertilized by a sperm cell from a man and the result is a single cell called a zygote. Over the next week, the zygote divides into multiple cells that form the developing embryo. At the end of that period, the embryo hatches out of its protective membrane and begins implanting itself into the lining of the mother’s uterus.

It’s possible to visualize the early stages of embryo development in culture dishes, which has helped scientists understand the biological steps required for an embryo to survive and develop into a healthy fetus. However, something that is not easy to observe is the implantation stage of the embryo in the uterus. This process is complex and involves a restructuring of the uterine wall to accommodate the developing embryo. As you can imagine, replicating these events would be extremely complicated and difficult to do in a culture dish, and current imaging techniques aren’t adequate either.

That’s where new CIRM-funded research from a team at UCSF comes to the rescue. They developed a 3D imaging technology and combined it with a previously developed “tissue clearing” method, which uses chemicals to turn tissues translucent, to provide clear images of the uterine wall during embryo implantation in mice. Their work was published this week in the journal Development.

According to a UCSF news release,

“Using their new approach, the team observed that the uterine lining becomes extensively folded as it approaches its window of receptivity for an embryo to implant. The geometry of the folds in which the incoming embryos dwell is important, the team found, as genetic mutants with defects in implantation have improper patterns of folding.”

Ultimately, the team aims to use their new imaging technology to get an inside scoop on how to prevent or treat pregnancy disorders and also how to improve the outcome of pregnancies by in vitro fertilization.

Senior author on the study, UCSF professor Diana Laird concluded:

“This new view of early pregnancy lets us ask fundamentally new questions about how the embryo finds its home within the uterus and what factors are needed for it to implant successfully. Once we can understand how these processes happen normally, we can also ask why certain genetic mutations cause pregnancies to fail, to study the potential dangers of environmental toxins such as the chemicals in common household products, and even why metabolic disease and obesity appears to compromise implantation.”

If you want to see this womb with a view, check out the video below.

Watch these two videos for more information:

Salk scientists reverse signs of aging in mice. For our next scintillating stem cell story, we’re turning back the clock – the aging clock that is. Scientists from the Salk Institute in La Jolla, reported an interesting method in the journal Cell  that reverses some signs of aging in mice. They found that periodic expression of embryonic stem cell genes in skin cells and mice could reverse some signs of aging.

The Salk team made use of cellular reprogramming tools developed by the Nobel Prize winning scientist Shinya Yamanaka. He found that four genes normally expressed in embryonic stem cells could revert adult cells back to a pluripotent stem cell state – a process called cellular reprogramming. Instead of turning adult cells back into stem cells, the Salk scientists asked whether the Yamanaka factors could instead turn back the clock on older, aging cells – making them healthier without turning them back into stem cells or cancer-forming cells.

The team found that they could rejuvenate skin cells from mice without turning them back into stem cells if they turned on the Yamanaka genes on for a short period of time. These skin cells were taken from mice that had progeria – a disease that causes them to age rapidly. Not only did their skin cells look and act younger after the treatment, but when the scientists used a similar technique to turn on the Yamanaka genes in progeria mice, they saw rejuvenating effects in the mice including a more rapid healing and regeneration of muscle and pancreas tissue.

(Left) impaired muscle repair in aged mice; (right) improved muscle regeneration in aged mice subjected to reprogramming. (Salk Institute)

(Left) impaired muscle repair in aged mice; (right) improved muscle regeneration in aged mice subjected to reprogramming. (Salk Institute)

The senior author on the study, Salk Professor Juan Carlos Izpisua Belmonte, acknowledged in a Salk news release that this is early stage work that focuses on animal models, not humans:

“Obviously, mice are not humans and we know it will be much more complex to rejuvenate a person. But this study shows that aging is a very dynamic and plastic process, and therefore will be more amenable to therapeutic interventions than what we previously thought.”

This story was very popular, which is not surprising as aging research is particularly fascinating to people who want to live longer lives. It was covered by many news outlets including STATnews, Scientific American and Science Magazine. I also recommend reading Paul Knoepfler’s journal club-style blog on the study for an objective take on the findings and implications of the study. Lastly, you can learn more about the science of this work by watching the movie below by the Salk.

Movie:

Stabilizing unstable stem cells. Our final stem cell story is brought to you by scientists from the UCLA Broad Stem Cell Research Center. They found that embryonic stem cells can harbor genetic instabilities that can be passed on to their offspring and cause complications, or even disease, later in life. Their work was published in two separate studies in Cell Stem Cell and Cell Reports.

The science behind the genetic instabilities is too complicated to explain in this blog, so I’ll refer you to the UCLA news release for more details. In brief, the UCLA team found a way to reverse the genetic instability in the stem cells such that the mature cells that they developed into turned out healthy.

As for the future impact of this research, “The research team, led by Kathrin Plath, found a way to correct the instability by resetting the stem cells from a later stage of development to an earlier stage of development. This fundamental discovery could have great impact on the creation of healthy tissues to cure disease.”

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

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

Bruce Conklin, Gladstone Institutes & UCSF

Bruce Conklin, Gladstone Institutes & UCSF

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

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

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

Scientists and Patient Advocates Speak Out

Malin Parmar, Lund University

Malin Parmar, Lund University

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

Adrienne Shapiro, Patient Advocate

Adrienne Shapiro, Patient Advocate

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

Henry Klassen (UC Irvine)

Henry Klassen, UC Irvine

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

Kristen MacDonald, RP patient

Kristen MacDonald, RP patient

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

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

Scientists and Patients need to work together

Don Kohn, Catriona Jamieson, Malin Parmar

Don Kohn, Catriona Jamieson, Malin Parmar

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

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

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

CIRM Public Stem Cell Event

CIRM Public Stem Cell Event

Good from bad: UCSF scientists turn scar-forming cells into healthy liver cells

Most people know that a healthy liver is key for survival. Unfortunately, maintaining a healthy liver isn’t always easy. There are more than 100 different types of liver disease caused by various factors like viral infection, obesity, and genetics. If left untreated, they can progress to end-stage liver disease, also known as cirrhosis, which effects more than 600,000 Americans and has a high mortality rate. While there is a cure in the form of liver transplantation, there aren’t enough healthy donors available to help out the number of patients who desperately need new livers.

Cirrhosis occurs when liver damage accumulates over time causing the development of scar tissue that eventually replaces healthy liver tissue and impairs liver function. The liver is an amazing organ and can function even with the build-up of scar tissue as long as at least 20% of its composition is healthy cells. This impressive nature is actually a problem because most patients with liver disease aren’t aware of their condition until its progressed past the point of no return.

What’s a damaged liver to do?

So what do patients with end-stage liver disease do if they can’t get a liver transplant? One answer comes in the form of regenerative medicine. Scientists can generate new healthy liver cells in a dish from stem cells derived from the skin cells of patients and could eventually transplant these cells into the damaged liver. However, a major roadblock that prevents this type of cell transplantation therapy from helping patients with liver disease is the built-up scar tissue that prevents the integration of these healthy cells into the damaged liver.

Scientists from UC San Francisco (UCSF) have come up with a new solution to this problem. In a CIRM-funded study published today in journal Cell Stem Cell, UCSF professor Holger Willenbring details a new approach to repairing damaged livers in mice – one that generates good, healthy liver cells from bad, scar-tissue forming cells already present in the damaged liver.

The bad cells in this case are called myofibroblasts. Initially, these cells play an important role in repairing injuries in the liver. They secrete proteins called collagen that form a support structure that helps maintain composition of the liver as it repairs itself. However, if liver damage persists as is the case with chronic injury, the excess buildup of collagen secreted by myofibroblasts causes the accumulation of permanent scar tissue or fibrosis, which can negatively impact liver function.

Reducing damage by improving function

Cirrhosis causing myofibroblast cells (red) are converted into healthy liver cells (green) to regenerate the damaged liver. (Willenbring lab)

Cirrhosis causing myofibroblast cells (red) are converted into healthy liver cells (green) to regenerate the damaged liver. (Willenbring lab)

In an “Ah-Ha” moment, Willenbring proposed that they could stop myofibroblasts in the damaged livers of mice from causing more fibrosis by turning them into healthy liver cells. Willenbring and his team used a specific type of virus called an adeno-associated virus that only infects myofibroblasts to deliver a cocktail of liver-specific genes that have the ability to transform cells into liver cells called hepatocytes. When they treated mice with end-stage liver disease with their viral cocktail, they observed that a small percentage of myofibroblasts were converted into hepatocytes that developed into new healthy liver tissue, which improved the overall liver function of these mice. They also tested their viral method on human myofibroblasts and found that it was successful in converting these cells into functional hepatocytes.

Willenbring explained the science behind their new technique in a UCSF news release:

“Part of why this works is that the liver is a naturally regenerative organ, so it can deal with new cells very well. What we see is that the converted cells are not only functionally integrated in the liver tissue, but also divide and expand, leading to patches of new liver tissue.”

Solution to a healthy liver?

It’s important to realize that these studies are still in their early stages. The UCSF team has plans to expand on their human cell studies and to improve their viral delivery method so that it is more specific to myofibroblasts and more efficient at converting these cells into functioning hepatocytes.

They also recognize that their strategy will not be the panacea for liver disease and cirrhosis. Willenbring commented:

“A liver transplant is still the best cure. This is more of a patch. But if it can boost liver function by just a couple percent, that can hopefully keep patients’ liver function over that critical threshold, and that could translate to decades more of life.”

However, their study does offer a number of advantages over cell transplant therapies for liver disease including repairing the liver and improving its function from within the organ itself and also offering a simpler and cheaper form of treatment that would be accessible to more patients.

Willenbring puts it best:

Holger Willenbring, UCSF

Holger Willenbring, UCSF

“The new results suggest that in the fibrotic liver, this approach could produce a more efficient and stable improvement of liver function than cell transplant approaches. Once the viral packaging is optimized, such a treatment could be done cheaply at a broad range of medical facilities, not just in the specialized research hospitals where stem-cell transplants could be conducted.”

UCSF Scientists find molecular link between brain stem cells and Zika Infection

The Zika virus scare came to a head in 2015, prompting the World Health Organization to declare the outbreak a global health emergency earlier this year. From a research standpoint, much of the effort has centered on understanding whether the Zika infection is actually a cause of birth defects like microcephaly and how the virus infects mothers and their unborn children.

The Zika Virus is spread by a specific type of mosquito, the Aedes aegypti.

The Zika Virus is spread to humans by mosquitos.

What’s known so far is that the Zika virus can pass from the mother to the fetus through the placenta and it can infect the developing brain of the fetus. But how exactly the virus infects brain cells is less clear.

Brain stem cells are vulnerable to Zika

Scientists from UC San Francisco (UCSF) are tackling this question and have unraveled one more piece to the Zika infection puzzle. UCSF professor Dr. Arnold Kriegstein and his team reported yesterday in the journal Cell Stem Cell that they’ve identified a protein receptor on the surface of brain stem cells that could be the culprit for Zika virus infection.

Based on previous studies that showed that the Zika virus specifically infects brain stem cells, Kriegstein and his colleagues hypothesized that these cells expressed specific proteins that made them vulnerable to Zika infection. They looked to see which genes were turned on and off in brain stem cells derived from donated fetal tissue as well as other cell types in the developing brain to identify proteins that would mediate Zika virus entry.

AXL is to blame

They found a protein receptor called AXL that was heavily expressed in a type of brain stem cell called the radial glial cell, which gives rise to the outer layer of the brain called the cerebral cortex. AXL piqued their interest because it was identified in other studies as an entry point for Zika and other similar viruses like dengue in human skin cells. Furthermore, the team confirmed that radial glial cells produce a lot of AXL protein during development and it appears during a specific window of time – the second trimester of pregnancy.

A link between radial glial cells and Zika infection made sense to first author Tomasz Nowakowski who explained in a UCSF news release,

“In the rare cases of congenital microcephaly, these [radial glial cells] are the cells that die or differentiate prematurely, which is one of the reasons we became interested in the possible link.”

The team also found that AXL was expressed in mature brain cells including astrocytes and microglia and in retinal progenitor cells in the eye. They pointed out that the presence of AXL in the developing eye could help explain why many cases of Zika infection are associated with eye defects.

Modeling Zika infection using mini-brains

The bulk of the study used stem cells isolated from donated human fetal tissue, but the team also developed a different stem cell model to confirm their results. They generated brain organoids, also coined as “mini-brains”, in a dish from human induced pluripotent stem cells. These mini-brains contain structures and cell types that closely resemble parts of the developing brain. The team studied radial glial like cells in the mini-brains and found that they also expressed AXL on their surface.

An image of tissue that’s grown in a dish shows radial glia stem cells that are red, neurons in blue and the AXL receptor in green. Photo by Elizabeth DiLullo

Mini-brains grown in a dish have radial glia stem cells (red), neurons (blue) and the AXL receptor (green). Photo by Elizabeth DiLullo, UCSF

Kriegstein and his team believe they now have a working stem cell model for how viruses like Zika can infect the brain. Using their brain organoid model, they plan to collaborate with other UCSF researchers to learn more about how Zika infection occurs and whether it really causes birth defects.

“If we can understand how Zika may be causing birth defects,” Kriegstein said, “we can start looking for compounds to protect pregnant women who become infected.”

What’s next?

While the evidence points towards AXL as one of the major entry points for Zika infection in the developing brain, the UCSF team and other scientists still need to confirm that this receptor is to blame.

Kriegstein explained:

Arnold Kriegstein, UCSF

Arnold Kriegstein, UCSF

“While by no means a full explanation, we believe that the expression of AXL by these cell types is an important clue for how the Zika virus is able to produce such devastating cases of microcephaly, and it fits very nicely with the evidence that’s available. AXL isn’t the only receptor that’s been linked with Zika infection, so next we need to move from ‘guilt by association’ and demonstrate that blocking this specific receptor can prevent infection.”

If AXL turns out to be the culprit, scientists will have to be careful about testing drugs that block its function given that AXL is important for the proliferation of brain stem cells during development. There might be a way however that such treatments could be given to at risk women before they get pregnant.


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