Stem cell byproducts provide insight into cure for spina bifida

A diagram of an infant born with spina bifida, a birth defect where there is an incomplete closing of the backbone portion of the spinal cord. Photo courtesy of the Texas Children’s Hospital website.

Some of you might remember a movie in the early 2000s by the name of “Miracle in Lane 2”. The film is based on an inspirational true story and revolves around a boy named Justin Yoder entering a soapbox derby competition. In the movie, Justin achieves success as a soapbox derby driver while adapting to the challenges of being in a wheelchair.

Scene from “Miracle in Lane 2”

The reason that Justin is unable to walk is due to a birth defect known as spina bifida, which causes an incomplete closing of the backbone portion of the spinal cord, exposing tissue and nerves. In addition to difficulties with walking, other problems associated with this condition are problems with bladder or bowel control and accumulation of fluid in the brain.

According to the Center for Disease Control (CDC) , each year about 1,645 babies in the US are born with spina bifida, with Hispanic women having the highest rate of children born with the condition. There is currently no cure for this condition, but researchers at UC Davis are one step closer to changing that.

Dr. Aijun Wang examining cells under a microscope. He has identified stem cell byproducts that protect neurons. Photo courtesy of UC Regents/UC Davis Health

Dr. Aijun Wang, Dr. Diana Farmer, and their research team have identified crucial byproducts produced by stem cells that play an important role in protecting neurons. These byproducts could assist with improving lower-limb motion in patients with spina bifida.

Prior to this discovery, Dr. Farmer and Dr. Wang demonstrated that prenatal surgery combined with connective tissue (e.g. stromal cells) derived from stem cells improved hind limb control in dogs with spina bifida. Below you can see a clip of two English bulldogs with spina bifida who are now able to walk.

Their findings were published in the Journal of the Federation of American Societies for Experimental Biology on February 12, 2019.

The team will use their findings to perfect the neuroprotective qualities of a stem cell treatment developed to improve locomotive problems associated with spina bifida.

In a public release posted by EurekaAlert!, Dr. Wang is quoted as saying, “We are excited about what we see so far and are anxious to further explore the clinical applications of this research.”

The discovery and development of a treatment for spina bifida was funded by a $5.66 million grant from CIRM. You can read more about that award and spina bifida on a previous blog post linked here.

Frustration, failure and finally hope in the search for treatments for spina bifida

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Dr. Diana Farmer and her team at UC. Davis

By any standards Dr. Diana Farmer is a determined woman who doesn’t let setbacks and failure deter her. As a fetal and neonatal surgeon, and the chair of the Department of Surgery at UC Davis Health, Dr. Farmer has spent years trying to develop a cure for spina bifida. She’s getting closer.

Dr. Farmer and her partner in this research, Dr. Aijun Wang, have already shown they can repair the damage spina bifida causes to the spinal cord, in the womb, in sheep and bulldogs. Last year the CIRM Board voted to fund her research to get the data needed to apply to the US Food and Drug Administration for permission to start a clinical trial in people.

That work is so promising that we decided to profile Dr. Farmer in our 2018 Annual Report.

Here’s excerpts from an interview we conducted with her as part of the Annual Report.

I have been working on this since 2008. We have been thinking about how to help kids with spina bifida walk. It’s not fatal disease but it is a miserable disease.

It’s horrible for parents who think they are about to have a healthy child suddenly be faced with a baby who faces a life long struggle with their health, everything from difficulty or inability to walk to bowel and bladder problems and life-threatening infections.

As a fetal surgeon we used to only focus on fatal diseases because otherwise kids would die. But as we made progress in the field, we had the opportunity to help others who didn’t have a fatal condition, in ways we couldn’t have done in the past.

I’ve always been fascinated by the placenta, it has lots of protective properties. So, we asked the question if we were able to sample fetal cells from the placenta, could we augment those cells, and use them to tissue engineer spinal injuries, in the womb, to improve the outcome for kids with spina bifida?

Dr. Aijun Wang and I have been working on this project for the last decade.  Ten years of work has taken us to this point where we are now ready to move this to the next level.

It’s amazing to me how long this process takes and that’s why we are so grateful to CIRM because this is a rare disease and finding funding for those is hard. A lot of people are scared about funding fetal surgery and CIRM has been a perfect partner in helping bring this approach, blending stem cell therapy and tissue engineering, together.

If this therapy is successful it will have a huge economic impact on California, and on the rest of the world. Because spina bifida is a lifelong condition involving many operations, many stays in the hospital, in some cases lifelong use of a wheelchair. This has a huge financial burden on the family. And because this doesn’t just affect the child but the whole family, it has a huge psychological burden on families. It affects them in so many ways; parents having to miss work or take time off work to care for their child, other children in the family feeling neglected because their brother or sister needs so much attention.

In the MOMS Trial (a study that looked at prenatal – before birth – and postnatal – after birth – surgery to repair a defect in the spinal cord and showed that prenatal surgery had strong, long-term benefits and some risks) we showed that we could operate on the fetus before birth and help them. The fact that there was any improvement – doubling the number of kids who could walk from 20 to 40% showed this spinal cord injury is not a permanent situation and also showed there was some plasticity in the spinal cord, some potential for improvement. And so, the next question was can we do more. And that’s why we are trying this.

It’s pretty amazing. We are pretty excited.

The thing that makes surgeon-scientists feel so passionate is that we don’t just ask the fundamental questions, we ask questions in order to cure a problem in patients. I grew up in an environment where people were always asking “how can we do it better, how can we improve?”

There were many times of frustration, many times when cell types we explored and worked with didn’t work. But it’s the patients, seeing them, that keeps me motivated to do the science, to keep persevering. That’s the beauty of being a clinician-scientist. We can ask questions in a different way and look at data in a different way because we are driven by patient outcomes. So, whenever we get stuck in the rabbit hole of theoretical problems, we look to the patients for inspiration to keep going.

I am very cognizant of stirring up false hope, knowing that what occurs in animal models doesn’t always translate into humans. But we are optimistic, and I am anxious to get going.

 

Promising Approach to Curing Spina Bifida Gets $5.6 Million from Stem Cell Agency

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Every day in the U.S. four children are born with spina bifida. It is the most common cause of lifelong paralysis and also frequently leads to other serious health problems affecting the bowel and bladder. The impact on families is enormous. A new approach to repairing the defect that causes spina bifida was today awarded $5.66 million by the Board of the California Institute for Regenerative Medicine (CIRM).

In spina bifida the spinal cord doesn’t form properly, in many cases leaving a section of it open, exposing tissues and nerves. The current standard of care is surgery, but even this leaves almost 60% of children unable to walk independently. Diana Farmer MD, and Aijun Wang PhD at U.C. Davis will use mesenchymal stem cells, taken from a donor placenta, and place them on a form of synthetic scaffold over the injury site in the womb. Tests in animals show this approach was able to repair the defect and prevent paralysis.

“Spina bifida is a devastating condition for babies born with this disorder and the families who care for them,” says Maria T. Millan, MD, President & CEO of CIRM. “CIRM has funded this important work from its earliest stages and we are committed to working with Dr. Farmer’s team to moving this work to the stage where it can be tested in patients.”

The CLIN1 award will provide funding to enable the UC Davis team to do the final testing and preparations needed to apply to the FDA for permission to start a clinical trial.

Dr. Farmer says she and Dr. Wang, have been working on this approach for more than ten years and are excited about being able to take the next step.

“There were many times of frustration, many times when cell types we explored and worked with didn’t work,” says Dr. Farmer. “But it’s the patients, seeing them, talking to them and working with them, that keeps me motivated to do the science, to keep persevering.”

If this therapy is successful it will have a huge economic impact on California, and on the rest of the world. Because spina bifida is a lifelong condition involving many operations, many stays in the hospital and, in some cases, lifelong use of a wheelchair this has a huge financial, and psychological, burden on the family.

“It affects them in so many ways; parents having to miss work or take time off work to care for their child, other children in the family feeling neglected because their brother or sister needs so much attention,” says Dr. Farmer. “That’s why we are so grateful to CIRM. Because this is a rare disease and finding funding for those is hard. CIRM has been a perfect partner in helping bring this approach, blending stem cell therapy and tissue engineering, together to help these families.”

This video shows English bulldogs treated with this approach who are now able to walk:

Hits and Myths as people celebrate Stem Cell Awareness Day

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Stem Cell Awareness Day at UC Davis

Every year, the second Wednesday in October is set aside as Stem Cell Awareness Day, a time to celebrate the progress being made in the field and to remind us of the challenges that lie ahead.

While the event began here in California in 2008, with then-Governor Arnold Schwarzenegger highlighting the work of CIRM, saying: ”The discoveries being made today in our Golden State will have a great impact on many around the world for generations to come.” It has since grown to become a global event.

Here in California, for example, UC Davis and the University of Southern California (USC) both held events to mark the day.

At UC Davis Jan Nolta, PhD., the Director of the Stem Cell Program, introduced a series of speakers who highlighted the terrific work being done at the university. Peter Belafsky talked about using stem cells to repair damaged trachea and to help people who are experiencing voice or swallowing disorders. Mark Lee highlighted the progress being made in using stem cells to repair hard-to-heal broken bones. Aijun Wang focused on some really exciting work that could one day lead to a therapy for spina bifida (including some ridiculously cute video of English bulldogs who are able to walk again because of this therapy.)

USC hosted 100 local high school students for a panel presentation and discussion about careers in stem cell research. The panel featured four scientists talking about their experience, why the students should think about a career in science and how to go about planning one. USC put together a terrific video of the researchers talking about their experiences, something that can help any student around the US consider becoming part of the future of stem cell research.

Similar events were held in other institutions around California. But the celebration wasn’t limited to the Golden State. At the Texas Heart Institute in Houston, Texas, they held an event to talk to the public about the clinical trials they are supporting using stem cells to help people suffering from heart failure or other heart-related issues.

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Finally, the UK-based RegMedNet, a community site that unites the diverse regenerative medicine community, marked the day by exploring some of the myths and misconceptions still surrounding stem cells and stem cell research.

You can read those here.

Every group takes a different approach to celebrating Stem Cell Awareness Day, but each is united by a common desire, to help people understand the progress being made in finding new treatments and even cures for people with unmet medical needs.

Stem cell treatment helps puppies born with spina bifida walk again

Just when you thought puppies couldn’t get any cuter, this video appears in your twitter feed.

These adorable English bulldog puppies are named Darla and Spanky, and they were born with a birth defect called spina bifida where the bones and tissue surrounding the spinal cord fail to fuse completely. Spina bifida occurs in 1500-2000 children in the US each year and can cause serious problems such as paralysis and issues with walking, cognition, and bladder or bowel control. Dogs born with this condition usually cannot use their hind legs, and as a sad consequence, are typically put down at a young age.

Cutting edge research from UC Davis is now giving these unfortunate puppies hope. Diana Farmer, a fetal surgeon at UC Davis Health, and scientists from the university’s Veterinary Institute for Regenerative Cures have developed a combination surgery and stem cell transplant, using placenta-derived mesenchymal stromal cells (PMSCs), to treat puppies with spina bifida. Because prenatal screening for spina bifida is not done in dogs, Darla and Spanky received the treatment when they were ten weeks old.

With funding from a CIRM preclinical development award, Farmer has done similar surgeries in lambs that are still in the womb. A UC Davis news release provided historical background on Farmer’s work on spina bifida,

“Farmer pioneered the use of surgery prior to birth to improve brain development in children with spina bifida. She later showed that prenatal surgery combined with human placenta-derived mesenchymal stromal cells (PMSCs), held in place with a cellular scaffold, helped research lambs born with the disorder walk without noticeable disability.”

As you can see from the video, the surgeries were a success. Darla and Spanky are now able to live up to their full puppy potential and will live happily ever after with their adoptive family in New Mexico.

Looking forward, Farmer and her team would like to treat more dogs with spina bifida so they can improve another negative consequence of spina bifida called incontinence, or an uncontrollable bladder. The UC Davis release explained that, “while Darla and Spanky are very mobile and doing well on their feet, they still require diapers.” (Side note: this video proves that puppies can make anything look cute, even dirty diapers.)

Additionally, the team is hoping to receive regulatory approval from the US Food and Drug Administration to launch a clinical trial testing this therapy in humans. If this stem cell treatment proves to be both safe and effective in clinical trials, it could potentially prevent spina bifida from ever happening in animals and in humans.

English Bulldog undergoing spina bifida surgery at UC Davis Veterinary Medical Teaching Hospital. (Gregory Urquiaga/UC Davis)

Stem cell repair of birth defect during pregnancy possible, rodent study shows

As far-fetched as it may sound, performing prenatal surgery on a fetus still growing inside its mother’s womb is actually possible. This specialized procedure is done to repair birth defects like spina bifida, in which a baby’s back bones don’t form properly around the spinal cord. This opening in the spine that leads to excess spinal fluid and leaves spinal cord nerve cells unprotected from the surrounding tissue.  These abnormalities can lead to brain damage, paralysis and loss of bladder control.

Although prenatal surgery to close up the defect can reduce future neurological problems in the child’s life, there is an increased danger of significant complications including preterm birth, separation of the placenta from the uterus and premature breaking on the amniotic membrane (ie breaking the mother’s water).

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Microscopy image of iSkin, three-dimensional cultured skin derived from human iPSCs. Credit: Kazuhiro Kajiwara.

A research team at Japan’s National Research Institute for Child Health and Development is trying to overcome these problems by developing a less invasive prenatal therapy for spina bifida using stem cells. And this week, they published a Stem Cell Reports study that shows encouraging preclinical results in rodents.

The most severe and common form of spina bifida called myelomeningocele usually leads to the formation of a fluid-filled bulge protruding from a newborn’s back. The team’s therapeutic approach is to graft 3D layers of stem cell-derived skin early in the pregnancy to prevent the bulge from forming in the first place. This minimally invasive procedure would hopefully be less risky than the surgical approach.

To demonstrate a proof of concept for this approach, skin graft experiments were performed on fetal rats that had myelomeningocele-like symptoms induced by the hormone retinoic acid. Human amniotic fluid cells collected from two pregnancies with severe fetal defects were used to derived human iPSCs which were then specialized into skin cells. Over a 14-week period – a timeline short enough to allow the eventual human procedure to be performed within the 28th to 29th week of pregnancy – the cells were grown into 3D layers they call, “iSkin”.

The iSkin grafts were transplanted in 20 fetal rats through a small cut into the wall of the uterus. At birth, the myelomeningocele defect in four rats was completely covered and partially covered in another eight rats. It’s encouraging to note that no tumors formed from the skin transplants, a concern when dealing with iPSC-derived cell therapies. In press release, team lead Dr. Akihiro Umezawa spoke about the promise of this approach but also the work that still lies ahead:

“We are encouraged by our results and believe that our fetal stem cell therapy has great potential to become a novel treatment for myelomeningocele. However, additional studies in larger animals are needed to demonstrate that our fetal stem cell therapy safely promotes long-term skin regeneration and neurological improvement.”